Clinical trial NCT03110575
Conditions: PTSD
Keywords: TNX-102 SL Bedtime Sublingual 3-month Safety Efficacy PTSD
Sponsor: Tonix Pharmaceuticals, Inc.
Start date: 2017-06-20; Completion date: 2018-07-27
Enrollment: 190 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, extension trial designed to evaluate safety over 12 additional weeks of TNX-102 SL therapy taken daily at bedtime for the treatment of PTSD. Patients recruited into this trial are those who have successfully completed the double-blind lead-in study.

Detailed description:
The study will consist of 5 study visits, including Screening/Baseline Visit 1 (Day 0, which is anticipated to be the same visit as the last visit on double-blind treatment), a phone visit after 2 weeks of treatment, and in-clinic visits after 4, 8, and 12 weeks of treatment.

The primary objective of the study is to evaluate the safety of TNX-102 SL tablets taken daily at bedtime over an additional 12 weeks in patients with PTSD who have completed a double-blinded lead-in study.

The secondary objective of the study is to evaluate the efficacy of TNX-102 SL tablets taken daily at bedtime over an additional 12 weeks in patients with PTSD who have completed a double-blinded lead-in study.

Arms: arm 1: 2 x TNX-102 SL, 2.8 mg tablets taken daily at bedtime for 12 weeks
Interventions: intervention 1: TNX-102 SL
Intervention descriptions: intervention 1: 2 x TNX-102 SL, 2.8mg tablets taken daily at bedtime for 12 weeks

Protocol documents:
Prot_000.pdf: 


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INVESTIGATOR’S AGREEMENT 
I have read the TNX-CY-P303 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: 
TNX-102 SL (Cyclobenzaprine HCl Sublingual Tablets) 
Name of Active Ingredient: 
Cyclobenzaprine HCl 
Title of Study: 
A 12-Week Open-Label Extension Study to Evaluate TNX-102 SL Taken Daily at Bedtime in 
Patients with PTSD 
 
Studied period (months): 20 
Estimated date first patient enrolled: June 2017 
Estimated date last patient completed: December 2018 
Phase of development: 3 
 
Objectives 
Primary: 
The primary objective of the study is to evaluate the safety of TNX-102 SL taken daily at bedtime 
over an additional 12 weeks in patients with PTSD who have completed a double-blind lead-in study. 
Secondary: 
The secondary objective of the study is to evaluate the efficacy of TNX-102 SL taken daily at 
bedtime over an additional 12 weeks in patients with PTSD who have completed a double-blind lead-
in study. 
Methodology:  
This is an open-label, extension trial designed to evaluate safety over 12 additional weeks of TNX-
102 SL therapy taken daily at bedtime for the treatment of PTSD. Patients recruited into this trial are 
those who have successfully completed a double-blind lead-in study.  Patients will not be made aware 
of the therapy they received during the double-blind study. 
The study will consist of 5 study visits, including Screening/Baseline Visit 1 (Day 0, which is 
anticipated to be the same visit as the last visit on double-blind treatment (final primary outcome visit 
in double-blind lead-in study)), a phone visit after 2 weeks of treatment and in-clinic visits after 4, 8, 
and 12 weeks of treatment.   
Eligible patients who provide written informed consent will be provided with two TNX-102 SL 2.8 
mg tablets to be taken daily at bedtime for 12 weeks.  Patient safety and efficacy parameters recorded 
at the final primary outcome visit of the double-blind lead-in study will be used as the baseline values 
for this extension study.  Patients will have a telephonic visit at week 2 and then return to the clinic 
after 4, 8 and 12 weeks of treatment for safety and efficacy assessments.  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. 
Number of patients (planned): Completers of the double-blind lead-in study 
Patients who complete the double-blind lead-in study and satisfy the entry criteria below will be 
eligible for this study if offered at their enrolling site.   


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Inclusion/Exclusion Criteria: 
Inclusion criteria: 
1. The patient has completed the final treatment study visit of the lead-in study 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. 
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, 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: 
Name: TNX-102 SL (cyclobenzaprine HCl sublingual tablets) 
Dose, route, frequency: 2 tablets of 2.8 mg of TNX-102 SL taken simultaneously and sublingually 
(under the tongue) each day at bedtime starting on Day 0 for 12 weeks. 
Duration of treatment: 
12 weeks 
Reference therapy, dosage and mode of administration: None 
Criteria for evaluation: 
The primary objective of the study is to evaluate the safety of treatment with TNX-102 SL 5.6 mg for 
an additional 12 weeks in patients with PTSD who have completed a double-blind lead-in study.  
Safety will be assessed by the monitoring and recording of AEs, clinical laboratory tests, vital signs, 


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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).  
Efficacy will continue to be assessed during 12 weeks of open-label treatment with the Clinician-
Administered PTSD Scale for DSM-5 (CAPS-5), the Clinician Global Impression of Improvement 
(CGI-I), the Sheehan Disability Scale (SDS) and the Patient Reported Outcomes Measurement 
Information System (PROMIS) sleep disturbance scale.  
Statistics 
Analysis Population:  
The Safety Population will comprise all patients who receive at least 1 dose of study drug. 
 
Treatment Groups: 
As an extension of a double-blind study, two treatment groups will be defined as follows: 
 
TNX-102 SL /TNX-102 SL treatment group:  patients who received TNX-102 SL in 
the double-blind lead-in study and then continued to receive TNX-102 SL in the 
extension study  
 
Placebo/TNX-102 SL treatment group:  patients who received placebo in the double-
blind study and then received TNX-102 SL in the extension study 
 
Patients and site personnel will not be informed concerning treatment assignments in the lead-in 
study, thus there will be a blinded crossover to active therapy in the extension study. 
 
Baseline: 
Baseline will be defined in two different ways as follows: (1) as the last measurement obtained prior 
to randomization in the double-blind lead-in study (i.e., the original baseline from the lead-in study); 
and (2) as the measurement obtained at the final primary outcome visit in the double-blind lead-in 
study and prior to enrollment into the P303 extension study (i.e., the measurement from the final visit 
of the double-blind lead-in study, which is the same as P303 Visit 1).  
 
Safety Analyses:   
Safety data will be summarized by treatment group.  Adverse events will be coded using the same 
version of the Medical Dictionary for Regulatory Activities (MedDRA) as used for the lead-in 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 at Week 12 
from the lead-in study will be transcribed into the eCRF.  All other adverse events that are reported 
after starting TNX-102 SL 5.6 mg in this extension study, or that worsen after entry into the extension 
study, will be considered newly emergent AEs (NEAEs), even if the type of event was previously 
reported (and resolved) during the lead-in study. 
Actual values and changes from both baselines for clinical laboratory test results, vital sign 
measurements, and in the BDI-II score will be summarized at endpoint using descriptive statistics (n, 
mean, SD, median, minimum, and maximum).  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. 
 
Efficacy Analyses: 


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Descriptive statistics by treatment group and study visit will be displayed for a number of efficacy 
endpoints, including: 
 
Change from both baselines in the total CAPS-5 score  
 
Proportion of patients with a CGI-I score of “very much improved” or “much improved” 
from both baselines 
 
Change from both baselines in the SDS total score  
 
Change from both baselines in the individual items assessed using the SDS 
 
Change from both baselines in patients’ quality of sleep using the PROMIS Sleep 
Disturbance scale  
 
Change from both baselines in CAPS-5 symptom cluster subscores 
 
Proportion of patients with a ≥50% improvement from baseline (both baselines) in total 
CAPS-5 score  
 
Change from both baselines in BDI-II score  
Hypothesis testing will also be performed on the above efficacy endpoints.  Missing values will not 
be imputed, and no adjustments will be made for multiplicity. 


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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 ..............................................18 
7.1. 
Informed Consent .......................................................................................................18 
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 ..............................................................................................20 
8.4. 
Release of Clinical Study Supplies to the Investigator ...............................................21 
8.5. 
Concomitant Medications ...........................................................................................21 
8.6. 
Study Drug Accountability and Reconciliation ..........................................................21 
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. 
Visit 1 Baseline Assessments/Procedures (Week 0) ..................................................23 
9.2. 
Visit 2 (Telephone Visit: Week 2) ..............................................................................24 
9.3. 
Visits 3 and 4 (Weeks 4 and 8) ...................................................................................25 
9.4. 
Visit 5 (Week 12) ........................................................................................................25 
9.5. 
Early Termination (ET) ..............................................................................................26 
9.6. 
Unscheduled Visits .....................................................................................................27 
10. 
STUDY ASSESSMENTS ..........................................................................................28 
10.1. 
Screening Assessments ...............................................................................................28 
10.2. 
Efficacy Assessments .................................................................................................28 
10.2.1. 
Clinician Administered PTSD Scale for DSM-5 (CAPS-5) .......................................28 
10.2.2. 
Clinical Global Impression of Improvement (CGI-I) .................................................28 
10.2.3. 
Sheehan Disability Scale (SDS) .................................................................................29 
10.2.4. 
PROMIS Sleep Disturbance Scale ..............................................................................29 
10.2.5. 
Beck Depression Index (BDI-II) ................................................................................29 
10.3. 
Safety Parameters .......................................................................................................29 
10.3.1. 
Adverse Events (AEs) .................................................................................................29 
10.3.1.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................30 
10.3.1.2. 
Safety Planning Intervention (SPI) .............................................................................30 
10.3.1.3. 
Visual Examination of Oral Cavity ............................................................................30 
10.3.1.4. 
Vital Signs ..................................................................................................................30 
10.3.1.5. 
Clinical Laboratory Assessments ...............................................................................31 
11. 
DEFINITIONS, RECORDING, AND REPORTING OF ADVERSE 
EVENTS AND PREGNANCY ..................................................................................32 
11.1. 
Definition of Adverse Events .....................................................................................32 
11.2. 
Adverse Event Recording ...........................................................................................32 
11.2.1. 
Coding the Adverse Event ..........................................................................................32 
11.2.2. 
Severity of Adverse Event ..........................................................................................32 
11.2.3. 
Relationship of Adverse Events to Study Drug ..........................................................33 
11.3. 
Serious Adverse Events (SAEs) and Serious Adverse Drug Reactions .....................33 
11.4. 
Pregnancy ...................................................................................................................35 
12. 
STATISTICS ..............................................................................................................36 
12.1. 
Evaluation of Safety ...................................................................................................36 


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12.2. 
Evaluation of Efficacy ................................................................................................36 
12.3. 
Estimate of Sample Size .............................................................................................37 
12.4. 
Assessment of Demographic and Baseline Characteristics and Patient 
Disposition ..................................................................................................................37 
12.5. 
Exploratory Analyses ..................................................................................................37 
13. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY .................................................................................38 
13.1. 
Protocol Modifications and Deviations ......................................................................38 
13.2. 
Study Termination ......................................................................................................38 
14. 
ETHICAL CONSIDERATIONS................................................................................39 
14.1. 
Ethical Conduct of the Study ......................................................................................39 
14.2. 
Ethics Committee/Institutional Review Board (EC/IRB) Review .............................39 
14.3. 
Written Informed Consent ..........................................................................................39 
15. 
DATA HANDLING AND RECORDKEEPING .......................................................41 
15.1. 
Maintaining Privacy and Confidentiality....................................................................41 
15.2. 
Maintaining Essential Clinical Documents ................................................................41 
15.3. 
Data Handling .............................................................................................................41 
15.4. 
Case Report Forms (CRFs) .........................................................................................42 
15.5. 
Screening Records ......................................................................................................42 
15.6. 
Clinical Laboratory Certification ................................................................................42 
15.7. 
Site Monitoring and Tonix’s Right to Review Records .............................................42 
15.8. 
Audits and Inspections ................................................................................................43 
16. 
CONFIDENTIALITY ................................................................................................44 
16.1. 
Protection of Patient Anonymity ................................................................................44 
16.2. 
Confidentiality of Study Information .........................................................................44 
16.3. 
Publication of Data and Protection of Trade Secrets ..................................................44 
17. 
LIST OF REFERENCES ............................................................................................46 
18. 
APPENDICES ............................................................................................................47 
APPENDIX 1. STUDY DESIGN AND SCHEDULE OF ASSESSMENTS .............................47 
APPENDIX 2. LIST OF CYP3A INHIBITORS ........................................................................49 
APPENDIX 3. AMRIX® PACKAGE INSERT (DATED MAY 2016) .....................................50 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Clinical Laboratory Assessments ...............................................................................31 
Table 3: 
Medical Monitoring Contact Information ..................................................................34 


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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 
CAPS-5 
Clinician Administered PTSD Scale (for DSM-5) 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression- Improvement from Initiation of Treatment 
CK 
Creatinine Kinase 
CoC 
Certificates of Confidentiality 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP3A4 
Cytochrome P450 subtype 3A4 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders (Version 5) 
e.g. 
Exempli gratia (for example) 
EC 
Ethics Committee 
ET 
Early Terminate 
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 Conference on Harmonisation 
IND 
Investigational New Drug 


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Abbreviation or 
Specialist Term 
Explanation 
IRB 
Institutional Review Board 
MCH 
Mean corpuscular hemoglobin 
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 
PI 
Principal Investigator 
PO 
per os (by mouth) 
PROMIS 
Patient-Reported Outcome Measurement Information System 
PTSD 
Post-Traumatic 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 
US 
United States 
VA 
Veteran’s Administration 
WBC 
White blood count 
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 safety of TNX-102 SL taken daily at 
bedtime over an additional 12 weeks in patients with PTSD who have completed a double-blind 
lead-in study. 
5.2. 
Secondary Objectives 
The secondary objective of the study is to evaluate the efficacy of TNX-102 SL taken daily at 
bedtime over an additional 12 weeks in patients with PTSD who have completed a double-blind 
lead-in study. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a 12-week, multicenter, open-label extension study designed to accumulate additional 
safety exposure and efficacy data 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 completed participation in a Phase 3, randomized, double-blind, placebo-
controlled study comparing TNX-102 SL 5.6 mg versus placebo for the treatment of PTSD will 
be eligible.  This extension study consists of 5 visits, including the Screening/Baseline visit 
(which is anticipated to be the same as the primary outcome visit in the double-blind lead-in 
study), a telephonic visit at week 2, and in-clinic visits after 4, 8 and 12 weeks of treatment 
(Visits 3-5).  The total treatment duration of this study will be 12 weeks.  Therefore, the 
maximum total duration of continuous treatment with TNX-102 SL could be approximately 24 
weeks for those patients assigned to active study drug in the lead-in study.  
Patient data collected at the Week 12 visit in the lead-in study will be used as one of the defined 
baselines for this study.  There is no need to repeat assessments at Visit 1 for this study, if they 
were collected in the lead-in study and patients enroll and initiate study treatment within fourteen 
days of completing the lead-in study. 
After the patient has completed his/her participation in the lead-in study and has consented to 
participate in this open-label extension study, patients will be dispensed a 4-week supply of 
open-label TNX-102 SL tablets and will be instructed to take the study drug sublingually daily at 
bedtime, starting on the evening of Visit 1.  A phone visit will be completed after 2 weeks of 
treatment and patients will return to the study center for safety and efficacy assessments at 
Weeks 4, 8, and 12 (or early termination).  At the Weeks 4 and 8 visits patients will return their 
TNX-102 SL medication and will receive another 4-week supply.  Patients will be allowed to 
take 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 
The total number of patients enrolled in this study depends on the number of completed patients 
from the lead-in study who qualify and consent to participate in this open-label extension study. 
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.  


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6.3. 
Study Endpoints 
6.3.1. 
Safety 
Safety will be assessed by: 
 Adverse events (AE) and serious AEs (SAEs) throughout the entire duration of the 
study, including assessment of AEs involving the oral cavity 
 Changes from both baselines in clinical laboratory test results 
 Changes from both baselines indicative of increased suicidal ideation or behavior as 
assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) 
 Change from both baselines in BDI-II 
 Changes from both baselines in vital signs and weight 
6.3.2. 
Efficacy  
Descriptive statistics by treatment group and study visit will be displayed for a number of efficacy 
endpoints including: 
 
 Change from both baselines in the total CAPS-5 score  
 Proportion of patients with a CGI-I score of “very much improved” or “much improved” 
from both baselines 
 Change from both baselines in the SDS total score  
 Change from both baselines in the individual items assessed using the SDS 
 Change from both baselines in patients’ quality of sleep using the PROMIS Sleep 
Disturbance scale  
 Change from both baselines in CAPS-5 symptom cluster subscores 
 Proportion of patients with a ≥50% improvement from baseline (both baselines) in total 
CAPS-5 score  
 Change from both baselines in BDI-II score 
Hypothesis testing will also be performed on the above efficacy endpoints.  Missing values will 
not be imputed, and no adjustments will be made for multiplicity. 


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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 
patient and by reviewing the patient’s experience in the double-blind lead-in study.  
Informed consent is documented by means of a written, signed, and dated informed consent form 
(ICF).  Additional information is provided in Section 14.3. 
7.2. 
Inclusion Criteria 
1. The patient has completed the final treatment study visit of the lead-in study 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. 
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, 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 
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 9.5. 


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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-P303, 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, two bottles will be dispensed to each patient at Visit 1 (baseline), Visit 3 
(Week 4) and Visit 4 (Week 8); this will provide the patient with 80 tablets to cover the 4 weeks 
of dosing 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 the second 
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 be instructed 
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 both 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 excursions 15-30°C/59-86°F are 
permitted with 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 12 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. 
8.3. 
Dispensing Instructions 
Each enrolled patient will be assigned 2 bottles of TNX-102 SL at each dispensing visit.  Bottles 
of TNX-102 SL tablets will be supplied to sites as open stock.   
 


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8.4. 
Release of Clinical Study Supplies to the Investigator 
Tonix or Tonix’s designee’s standard operating procedures 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 particular 
antidepressants, mood stabilizers, anticonvulsants, benzodiazepines, stimulants, and opioids, if 
needed.  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) (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 related 
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 treatment).  
8.6. 
Study Drug Accountability and Reconciliation 
All patients will be expected to bring their bottles of study medication with them to all study 
visits.  The site staff will inspect the medication bottles, perform a count of the tablets remaining 
in the bottles, and document this 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 
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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 Case Report Form (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. 
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.  This visit date is intended to be the same 
date as the final primary outcome endpoint of the lead-in study (Week 12); however, if there are 
extenuating circumstances, Visit 1 of P303 may occur within fourteen days of completion of the 
lead-in study without repeating baseline assessments.   If more than fourteen days elapse 
between the final visit of the lead-in study and start of the P303 study, baseline assessments will 
need to be repeated. 
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.  The patient should be dispensed two bottles of TNX-102 SL tablets, along with 
instructions on usage.  The end-of-study information collected in the double-blind lead-in study 
will be considered the baseline values for Study P303. 
9.1.3. 
Patient Numbering 
All patients who complete the double-blind lead-in study will retain their original concatenated 
6-digit site-patient number.  A log documenting the following information will be recorded and 
maintained at the study site:  patient’s initials, 6-digit identification number, and whether or not 
the patient met inclusion criteria and received open-label study medication.  If the patient did not 
meet these requirements, then the reason(s) for exclusion from the study should be documented. 
9.1.4. 
Visit 1 Baseline Assessments/Procedures (Week 0) 
The following assessments/procedures will be completed at Visit 1.  If assessments were 
collected as part of the final visit for the double-blind lead-in study, they will not need to be 
repeated. 
 Obtain written informed consent to participate 
 Inclusion criteria 


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 Review and transcribe new concomitant medications as well as those which are to be 
continued from the final visit of the double-blind lead-in study  
 Review and transcribe new AEs as well as those which are ongoing from the final 
visit of the double-blind lead-in study 
 Review findings obtained at the final visit of the double-blind lead-in study, including 
visual exam of the oral cavity, vital signs, and weight. The height collected at 
baseline from the lead-in study will be utilized for BMI calculations in this study.  
 Review results of the Beck Depression Inventory (BDI-II) and Columbia-Suicide 
Severity Rating Scale (C-SSRS) completed at the final visit of the double-blind lead-
in study. 
 Review all clinical laboratory test results obtained at the final visit of the double-blind 
lead-in study within 7 days of their release from the central lab (serum chemistries, 
hematology). Confirm negative urine pregnancy test (for women of child-bearing 
potential) obtained at the final visit of the double-blind lead-in study.  
 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.   
 The following assessments were completed as part of the final visit of the double-
blind lead-in study:  CAPS-5, PROMIS, and SDS.     
Only those patients meeting all of the inclusion criteria will be eligible to continue.  After all 
study requirements for Visit 1 of P303 have been fulfilled, the patient will:  
 Be dispensed two 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 and receive an appointment to return to the clinic for 
Visit 3. 
9.2. 
Visit 2 (Telephone Visit: Week 2) 
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 adverse events, including any oral adverse events and whether 
an unscheduled visit is indicated for an examination of the oral cavity 
 Review patient instructions regarding drug dosing  


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 Administer the ‘Since Last Visit’ C-SSRS telephonically 
9.3. 
Visits 3 and 4 (Weeks 4 and 8) 
These visits are conducted after 4 and 8 weeks (28 ± 7 and 56 ± 7 days) of treatment 
respectively.  The following assessments and procedures are to be conducted at each of these 
visits in the following general order:  
 Assess for occurrence of AEs  
 Perform and document an examination of the oral cavity if any oral AEs have been 
reported  
 Assess for changes in concomitant medications  
 Patient scales 
− BDI-II 
 Clinician Administered Scales  
− C-SSRS  
− CGI-I considering both baselines  
 Vital signs and weight 
 Urine pregnancy test (for women of child-bearing potential)  
 Collect returned study medication from patient  
 Perform drug accountability 
 Assess study drug compliance  
 Dispense 2 new bottles of TNX-102 SL tablets   
Review patient instructions regarding drug dosing and schedule appointment for next clinic visit.  
9.4. 
Visit 5 (Week 12) 
Visit 5 is to be conducted after 12 weeks (84 ± 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:  
 Assess for occurrence of AEs  
 Assess for changes in concomitant medications  
 Patient scales 
− BDI-II 
− SDS  
− PROMIS sleep disturbance  
 Clinician Administered Scales  
− C-SSRS  


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− CAPS-5  
− CGI-I considering both baselines 
 Vital signs and weight   
 Visual inspection of the oral cavity  
 Clinical laboratory tests  
 Urine pregnancy test (for women of child-bearing potential)  
 Assess and document study drug compliance  
9.5. 
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 adverse event (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:  
 Assess for occurrence of AEs  
 Assess for changes in concomitant medications  
 Patient scales 
− BDI-II 
− SDS  
− PROMIS sleep disturbance  
 Clinician Administered Scales  
− C-SSRS  
− CAPS-5  
− CGI-I considering both baselines 


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 Vital signs and weight   
 Visual inspection of the oral cavity  
 Clinical laboratory tests  
 Urine pregnancy test (for women of child-bearing potential)  
 Assess and document study drug compliance  
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 adverse event or 
other condition. 
9.6. 
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.  If an 
additional study visit occurs, the date and nature of the visit will be documented in the CRF and 
in the source documents. 


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10. 
STUDY ASSESSMENTS 
10.1. 
Screening Assessments 
Most screening assessments will be completed as part of the Week 12 visit of the lead-in study, 
as outlined in Section 9.1.4.  The results of these 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 study 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 
The assessment of efficacy is a secondary objective of this study 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.  
NOTE:  All of the assessments required for Visit 1 will come from the results at the final visit of 
the double-blind lead-in study as long as the patient enrolls within 14 days of the final visit of the 
double-blind lead-in study.  Only if the timeframe is longer than 14 days would there be a need 
to repeat these assessments.  
10.2.1. 
Clinician Administered PTSD Scale for DSM-5 (CAPS-5)   
The CAPS-5 symptom severity 1-week recall version will be administered by qualified and 
trained clinicians at the final visit of the double-blind lead-in study and at the final clinic study 
visit (Weeks 12).  In an attempt to minimize variability in the rating of CAPS-5 responses over 
time and between the lead-in and extension (P303) studies, as much as possible the same rater 
who performed the CAPS-5 throughout the lead-in study should also administer this assessment 
for the final visit in P303. Additional information regarding the conduct, rating, and scoring of 
the CAPS-5 instrument as well as the requirements for rater training will be provided separately.   
10.2.2. 
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, which for this study will be defined in two ways: (1) from 
the baseline visit of the lead-in double-blind study and (2) from the baseline visit of the extension 
study.  The CGI-I will be completed at each clinic visit.  It will be the responsibility of the 
Principal Investigator or his qualified designee to assess change in the subject’s overall status 
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10.2.3. 
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 
Baseline (Visit 1) and endpoint (Visit 5). 
10.2.4. 
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 Baseline 
(Visit 1) and endpoint (Visit 5).  
10.2.5. 
Beck Depression Index (BDI-II) 
BDI-II refers to the patient-rated assessments of depressive symptomology.  The BDI-II will be 
administered at Baseline (Visit 1) and Visits 3, 4, and endpoint (Visit 5). 
10.3. 
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, and patient-rated 
assessments of depressive symptomology (BDI-II).  
10.3.1. 
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.  


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10.3.1.1. 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 10.3.1.2 and an AE should be recorded.       
10.3.1.2. 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 
appropriate emergency care.  A score of 4 or 5 should also result in the reporting of a serious 
adverse event.   
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 U.S. 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.  
10.3.1.3. Visual Examination of Oral Cavity  
A visual examination of the oral cavity should be done at Baseline (Visit 1) and after 12 weeks 
(Visit 5) of treatment and/or at Early Termination.  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 an oral adverse event (other than numbness, tingling or bitter 
taste) in order to document 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.  
10.3.1.4. Vital Signs  
Vital signs (sitting blood pressure and heart rate, respiratory rate, oral temperature, and weight) 
will be assessed at Visits 1, 3, 4 and 5.  Height will be transferred from the lead-in study 
database, and BMI for the P303 baseline and Visit 5 will be calculated using height from the 
lead-in study baseline and weights from P303 baseline and Visit 5, respectively.  


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10.3.1.5. 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) and after 12 weeks of treatment (Visit 5), or Early 
Termination.  
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  
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)  
WBC differential  
Creatine 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)  
White blood cell (WBC) count  
Sodium  
  
Urine Pregnancy Test (qualitative 
dipstick)a  
   
a Pregnancy testing for females of child-bearing potential only.  A positive pregnancy test mandates withdrawal 
from the study (all visits). 


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11. 
DEFINITIONS, RECORDING, AND REPORTING OF ADVERSE 
EVENTS AND PREGNANCY 
11.1. 
Definition of Adverse Events 
According to International Conference on Harmonisation (ICH) guidance E2A, Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting, an adverse event (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 
baseline visit for P303, or any ongoing AE that was first reported during the lead-in study and 
which then exhibits an increase in severity, frequency or relationship after the patient’s 
participation in P303 has begun.  NEAEs and “All AEs” will be tallied by SOCs and preferred 
terms.  Adverse events that are ongoing at the time of the patient’s baseline visit for P303 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.  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 


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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 
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 


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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 
descriptions.  These should include copies of hospital case records and other documents when 
requested.  The 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: 
 


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For questions pertaining to the reporting of SAEs or the completion of SAE documentation, 
site personnel should call 
 
The investigator, or the sponsor or designee in the case of a central Institutional Review Board 
(IRB), also must notify the EC (Ethics Committee)/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. 
11.4. 
Pregnancy 
The active pharmaceutical product 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 complete description of the statistical analyses to be performed will be provided in a statistical 
analysis plan (SAP), which will be finalized prior to database lock. Two baselines for analysis 
are defined:  
1. Baseline 1: the original baseline randomization scores from the lead-in study.  
2. Baseline 2: baseline scores from Visit 1 of this study, which will be the same scores as 
the final endpoint efficacy scores from the Week 12, final primary outcome visit from 
the lead-in study.  
12.1. 
Evaluation of Safety  
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). 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and will be summarized overall and by preferred term and system organ class. 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.  
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.  
12.2. 
Evaluation of Efficacy  
Missing values will not be imputed, and no adjustments will be made for multiplicity in this 
extension study. Descriptive statistics (n, mean, SD, standard error of the mean, median, 
minimum, and maximum) will be displayed by the treatment received in the double-blind lead-in 
study and for all patients in the current study for the following efficacy parameters:  
 
 Change from both baselines in the total CAPS-5 score  
 Proportion of patients with a CGI-I score of “very much improved” or “much 
improved” from both baselines 
 Change from both baselines in the SDS total score  
 


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 Change from both baselines in the individual items assessed by the SDS 
 Change from both baselines in patients’ quality of sleep using the PROMIS Sleep 
Disturbance scale  
 Change from both baselines in CAPS-5 symptom cluster subscores 
 Proportion of patients with a ≥50% improvement from baseline (both baselines) in 
total CAPS-5 score  
 Change from both baselines in BDI-II score  
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 complete the lead-in 
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 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 summarized.  
12.5. 
Exploratory Analyses  
Efficacy results for the CAPS-5 will be compared between the patients who were treated with 
TNX-102 SL and those treated with placebo during the double-blind lead-in study.  


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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 Good Clinical Practices (GCP) guidelines, Good Laboratory Practices (GLP) 
guidelines, local ethical and regulatory requirements, including the Federal Food, Drug and 
Cosmetic Act, U.S. applicable Code of Federal Regulations (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. 


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The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH Good Clinical Practice (GCP) guidelines, the requirements of 21 CFR Part 50, 
“Protection of Human Patients,” the Health Insurance Portability and Accountability Act 
(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. 


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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. 
15.3. 
Data Handling 
Unless otherwise specified, procedures, data collection and evaluation will be conducted as per 
the Standard Operating Procedures (SOPs) of the contract research organization (CRO).  The 


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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. 
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. 


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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, Certificates of Confidentiality 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 
Clinic Visits 
Visit 
1a 
2e 
3 
4 
5 
Study Week 
0 
2 
4 
8 
12 
Study Day 
0 
14 ± 3 
28 ± 7  
56 ± 7 
84 ± 7 
Informed Consent 
X 
 
 
 
 
Inclusion Criteria  
X 
 
 
 
 
Psychiatric Treatment History (From lead-in study)  
X 
 
 
 
 
Demographics and Medical History (From lead-in 
study) 
X 
 
 
 
 
Concomitant Medicationsb 
X 
X 
X 
X 
X 
Vital Signs and weight  
X 
 
X 
X 
X 
Inspection of oral cavity 
Xc 
 
 
 
X 
Pregnancy Testd 
X 
 
X 
X 
X 
Clinical Laboratory Assessments 
X 
 
 
 
X 
BDI-II 
X 
 
X 
X 
X 
CAPS-5  
X 
 
 
 
X 
C-SSRS 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
PROMIS-sleep (short form) 
X 
 
 
 
X 
SDS 
X 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
Telephone Visite 
 
X 
 
 
 
Dispense Study Drug 
X 
 
X 
X 
 
Collect/ Count Study Drug Returned 
 
 
X 
X 
X 
 
Abbreviations:  BDI-II = Beck Depression Inventory-II; CAPS-5 = Clinician Administered PTSD Scale (for DSM-
5); 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  
 
a Assessments scheduled at this visit do not need to be repeated if they were completed during the final visit of the 
lead-in study. 
b Medications that are ongoing at end of lead-in 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. 


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eWeek 2 visit will be performed via telephone.  The patient will be asked about Adverse Events (including oral 
AEs), any change in medication, and study drug dosing and compliance and conduct the C-SSRS. 


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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.  
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 
CYP3A 
Boceprevir 
clarithromycin  
conivaptan 
grapefruit juice  
indinavir  
itraconazole 
ketoconazole,  
lopinavir/ritonavir 
mibefradil 
nefazodone 
nelfinavir 
posaconazole 
ritonavir  
saquinavir  
telaprevir 
telithromycin 
voriconazole 
 
amprenavir 
aprepitant 
atazanavir 
ciprofloxacin 
crizotinib 
darunavir/ritonavir 
diltiazem 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit juice  
imatinib 
verapamil 
alprazolam 
amiodarone 
amlodipine 
atorvastatin 
bicalutamide 
cilostazol 
cimetidine 
cyclosporine 
fluoxetine 
fluvoxamine 
gingko 
goldenseal  
isoniazid 
lapatinib 
nilotinib 
oral contraceptives 
pazopanib 
ranitidine 
ranolazine 
tipranavir/ritonavir 
ticagrelor 
zileuton 
 


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SAP_001.pdf: 


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DOCUMENT HISTORY
 


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SIGNATURE PAGE AND APPROVALS


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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................2
SIGNATURE PAGE AND APPROVALS .......................................................................3
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 .......................................................................8
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 .............................10
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-Administered PTSD Scale for DSM-5 (CAPS-5) ..........15
7.2.2
Clinician Global Impression of Improvement (CGI-I) ..................16
7.2.3
Sheehan Disability Scale (SDS) .....................................................16
7.2.4
Other Efficacy Outcomes ...............................................................17
7.3
Safety Assessments ....................................................................................17
7.3.1
Adverse Event and Prior/Concomitant Medication handling 
conventions ....................................................................................17


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8.
STUDY PARTICIPANTS AND DEMOGRAPHICS .......................................19
8.1
Disposition of Participants and Withdrawals .............................................19
8.2
Protocol Deviations....................................................................................19
8.3
Demographics and Other Baseline Characteristics ....................................19
9.
EFFICACY ANALYSES ....................................................................................20
9.1
Continuous Outcomes ................................................................................20
9.1.1
Efficacy Analysis Model................................................................20
9.1.2
Categorical outcomes .....................................................................21
10.
SAFETY AND TOLERABILITY ANALYSIS .................................................21
10.1
Adverse Events ..........................................................................................22
10.1.1 Adverse Events Leading to Discontinuation of Study Drug ..........23
10.1.2 Serious Adverse Events .................................................................23
10.1.3 Deaths ............................................................................................23
10.2
Clinical Laboratory Evaluations ................................................................23
10.3
Columbia Suicide Severity Rating Scale (C-SSRS) ..................................23
10.4
Vital Signs ..................................................................................................24
10.5
Visual Examination of Oral Cavity............................................................24
11.
MEDICATIONS ..................................................................................................25
11.1
Concomitant Medication ............................................................................25
11.2
Exposure and Compliance .........................................................................25
12.
CHANGES FROM PLANNED ANALYSIS .....................................................26
13.
REFERENCES .....................................................................................................27
14.
APPENDICES ......................................................................................................28
14.1
Appendix 1 .................................................................................................28
14.1.1 General Reporting Conventions .....................................................28
14.1.2 Population Summary Conventions ................................................29
14.2
Appendix 2: PROMIS T-score Conversions..............................................30
14.3
Appendix 3:  Abuse Terms ........................................................................31


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ABBREVIATIONS
ABBREVIATION
DEFINITION OR DESCRIPTION
AE
Adverse Event
ADaM
Analysis Data Model
ANCOVA 
Analysis of Covariance 
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 


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SAE
Serious Adverse Event 
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 
TNX-102 SL
Cyclobenzaprine HCl sublingual tablets
WHO-DD
World Health Organization Drug Dictionary 


Protocol: TNX-CY-P303                                                                                 Page 8 of 33 
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1. OVERVIEW 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for 
protocol 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. 
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. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective of the study is to evaluate the safety of TNX-102 SL taken daily at 
bedtime over an additional 12 weeks in patients with PTSD who have completed a 
double-blind lead-in study. 
2.1.2 Secondary Objectives 
The secondary objective is to evaluate the safety of TNX-102 SL 5.6 mg taken at bedtime 
over 12 weeks of treatment. 


Protocol: TNX-CY-P303                                                                                 Page 9 of 33 
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2.2 Study Endpoints 
2.2.1 Efficacy Endpoints  
Comparisons will be made at each study week of data collection to both the baseline of 
this study (P303) and the baseline from the double-blind study (P301) and described in 
section 7.1. 
Efficacy endpoints include:  
 Change from both baselines in the total CAPS-5 score 
 Proportion of patients with a CGI-
 
 from both baselines 
 Change from both baselines in the SDS total score 
 Change from both baselines in the individual items assessed using the SDS 
 
Sleep Disturbance scale 
 Change from both baselines in CAPS-5 symptom cluster subscores 
 
baselines) in total 
 CAPS-5 score 
 Change from both baselines in BDI-II score 
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 both baselines in clinical laboratory test results. 
 Changes from both baselines in vital signs and weight. 
 Change from both baselines in BDI-II. 
 Suicidal ideation or behavior as reported on the Columbia Suicide Severity 
Rating Scale (C-SSRS). 
 
 


Protocol: TNX-CY-P303                                                                                 Page 10 of 33 
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3. OVERALL STUDY DESIGN AND PLAN 
This is a 12-week, multicenter, open-label extension study designed to accumulate 
additional safety exposure and efficacy data 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 completed participation in a Phase 3, randomized, double-blind, 
placebo controlled study comparing TNX-102 SL 5.6 mg versus placebo for the 
treatment of PTSD will be eligible. This extension study consists of 5 visits, including the 
Screening/Baseline visit (which is anticipated to be the same as the primary outcome visit 
in the double-blind lead-in study), a telephonic visit at week 2, and in-clinic visits after 4, 
8 and 12 weeks of treatment (Visits 3-5). The total treatment duration of this study will 
be 12 weeks. Therefore, the maximum total duration of continuous treatment with TNX-
102 SL could be approximately 24 weeks for those patients assigned to active study drug 
in the lead-in study. 
Patient data collected at the Week 12 visit in the lead-in study will be used as one of the 
defined baselines for this study. There is no need to repeat assessments at Visit 1 for this 
study, if they were collected in the lead-in study and patients enroll and initiate study 
treatment within fourteen days of completing the lead-in study. After the patient has 
completed his/her participation in the lead-in study and has consented to participate in 
this open-label extension study, patients will be dispensed a 4-week supply of open-label 
TNX-102 SL tablets and will be instructed to take the study drug sublingually daily at 
bedtime, starting on the evening of Visit 1. A phone visit will be completed after 2 weeks 
of treatment and patients will return to the study center for safety and efficacy 
assessments at Weeks 4, 8, and 12 (or early termination). At the Weeks 4 and 8 visits 
patients will return their TNX-102 SL medication and will receive another 4-week 
supply. Patients will be allowed to take 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 initial protocol 
issued March 17, 2017 and Amendment 1, dated March 31, 2017. 
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. 


Protocol: TNX-CY-P303                                                                                 Page 11 of 33 
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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  
Any post-hoc, exploratory analyses completed to support planned study analysis, which 
were not identified in this SAP, will be documented and reported in appendices to the 
CSR.  Any results from these unplanned analyses (post-hoc) will also be clearly 
identified in the text of the CSR. 
 


Protocol: TNX-CY-P303                                                                                 Page 12 of 33 
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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. 
 


Protocol: TNX-CY-P303                                                                                 Page 13 of 33 
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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. 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 safety analyses and demographic/baseline 
characterization will be performed using this population.  
 
 


Protocol: TNX-CY-P303                                                                                 Page 14 of 33 
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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 that the 
subjects were randomized to in the prior study 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.  
Two baselines will be utilized for most analyses: P301 baseline values are defined as the 
last non-missing measurement prior to the first dose of double-blind study drug in study 
P301; likewise, P303 baseline values are defined as the last non-missing measurement 
prior to the first dose of open-label study drug in study P303.  Change from baseline will 
be defined as the post-baseline visit value minus the baseline value and will be calculated 
for both baselines.   
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 4, 8 or 12).  Visit 
windows will be assigned by splitting the periods between visits at the midpoint between 


Protocol: TNX-CY-P303                                                                                 Page 15 of 33 
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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.   
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-Administered PTSD Scale for DSM-5 (CAPS-5) 
The primary efficacy endpoint is the change from baseline in total CAPS-5 score at Week 
12 (Visit 6).  
The CAPS-5 is an updated and validated version of a semi-structured interview that has 
been designed to assess the essential features of PTSD as defined by the DSM-5 
(Weathers et al, 2013).  The CAPS-5 affords the clinician flexibility to inquire about 
symptoms and diagnostic status over different time frames, such as past week, past 
month, and/or worst month for lifetime.  
CAPS-5 (past month recall) will be utilized at the Screening visit to confirm the diagnosis 
-5 (past 
week recall) will be completed by the clinician at all other time points (Baseline [Visit 2] 
and after 12 weeks of treatment [Visits 6]).  
The CAPS-5 interview contains the following components 
 Life Events Checklist for DSM-5 (LEC-5): Completed by the participant at the 
Screening Visit (Visit 1 only) 
 Criterion A  Assessment Form (CA-AF):  this semi-structured interview is 
based on the Criterion A discussion included in the CAPS-5, but modified (by 
Dr. Frank Weathers, CAPS-5 lead author) specifically for this study to ensure 
sufficient review of the traumas outlined on the participant-completed LEC-5 
and to capture clear description of the participant s index/qualifying trauma 
(Visit 1 only) 
 PTSD symptoms, onset/duration, distress/impairment, global rating, and 
dissociative symptoms: 
o Criterion B: Items 1-5 (Intrusion symptoms) 
o Criterion C: Items 6-7 (Avoidance symptoms) 
o Criterion D: Items 8-14 (Negative alterations in cognitions & mood) 
o Criterion E: Items 15-20 (Arousal and reactivity symptoms) 
o Criterion F: Items 21-22 (Onset and duration of symptoms) 
o Criterion G: Items 23-25 (Distress and impairment due to PTSD) 
o Global ratings: Items 26-27 (Validity, severity) 
o Dissociative symptoms: Items 29 (Depersonalization) and 30 
(Derealization) 
In addition to the total symptom score (obtained from the sum of Criteria B-E), the 
CAPS-5 affords the opportunity to examine clusters of symptoms, including Criterion B 


Protocol: TNX-CY-P303                                                                                 Page 16 of 33 
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(intrusion symptoms), Criterion C (persistent avoidance), Criterion D (negative 
cognitions and mood), and Criterion E (arousal and reactivity), all of which will be 
secondary efficacy endpoints.  
In the case of CAPS-5 items that are not resolvable at the site level (via query, review of 
source), the following conventions will be employed for handling of missing CAPS-5 
items: 
 
 in Criterion B, D, or E, the average of the other 
items within the criterion will be used for the missing item;  
 For < 2 missing items scores in Criterion C, which only has 2 items, the value of 
the non-missing items will be used for the missing item;  
 For > 2 missing items in Criterion B, D, or E, or > 1 missing item in the 
Criterion C, the total CAPS-5 score will be considered missing overall. 
7.2.2 Clinician Global Impression of Improvement (CGI-I) 
The CGI-I will be completed by an Investigator to evaluate the participant
status since 
initiation of treatment.  The CGI-I, status since initiation of treatment, is the first key 
secondary efficacy endpoint in this study.  The CGI-I should be completed toward the 
end of each in-clinic post-Baseline study visit once all other assessments are available for 
Once the participant has been randomized, an Investigator 
completes the CGI-I assessment after 4, 8, and 12 weeks of treatment in order to assess 
the overall change in the participant
 
Since the initiation of treatment at Visit 2, 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 key secondary 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. 
7.2.3 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 two 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 12 weeks of treatment 
(Visits 6). A total score will be calculated summing the three individual 11-point (0-10) 


Protocol: TNX-CY-P303                                                                                 Page 17 of 33 
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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 two 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. 
7.2.4 Other Efficacy Outcomes 
7.2.4.1 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.  
The PROMIS sleep disturbance scale (short form 8a) will be assessed at Baseline and 
after 12 weeks of treatment (Visits 6). 
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 14.2). 
7.2.4.2 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 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 both baselines in clinical laboratory test results. 
 Changes from both baselines in vital signs and weight. 
 Change from both baselines in BDI-II (see Section 7.2.4). 
 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 AE and prior/concomitant medication dates, the following 
rules will be applied. 
For partial start dates: 


Protocol: TNX-CY-P303                                                                                 Page 18 of 33 
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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.  
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. 
  


Protocol: TNX-CY-P303                                                                                 Page 19 of 33 
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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. 
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).  In addition to the safety 
population, these will also be repeated for all randomized participants and the 
mITT population. 
 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 is 
collected in the lead-in study; this analysis displays that information for the population of 
subjects that entered this study. 
 


Protocol: TNX-CY-P303                                                                                 Page 20 of 33 
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9. EFFICACY ANALYSES 
9.1 Continuous Outcomes 
The mean change from each 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 each in 
outcome at each post-randomization visit.  
9.1.1 Efficacy Analysis Model 
Continuous endpoints collected at baseline and Week 12 will be analyzed in an analysis 
of covariance model (ANCOVA) for the change from each baseline (P301 baseline and 
P303 baseline) in separate, independent models. The model will include all participants in 
the safety population, and the dependent variable will be the observed change from each 
baseline to Week 12. Covariates in the model will include the fixed categorical effects of 
treatment, site, sex, current tobacco use status, presence of current MDE, as well as the 
continuous fixed covariate of baseline score. 
The least squares means and 95% confidence intervals (CIs) will be calculated for the 
treatment difference between the subjects that received TNX-102 SL and placebo in the 
lead-in study at each time point. 
Endpoints reported in this manner will include: 
 CAPS-5 Total 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 CAPS-5 Arousal and Reactivity (Criterion E).  
 Change from baseline in CAPS-5 Intrusion symptoms (Criterion B).  
 Change from baseline in CAPS-5 Negative Cognition and Mood (Criterion 
D).  
 Change from baseline in CAPS-5 Persistent Avoidance (Criterion C).  
 Change from baseline in CAPS-5 Sleep Disturbance (item E-6). 
 Change from baseline in CAPS-5 Exaggerated Startle (item E-4). 
 Change from baseline in CAPS-5 Reckless or Self-Destructive Behavior (item 
E-2). 
 Change from baseline in CAPS-5 Depersonalization (item 29). 
 Change from baseline in CAPS-5 Derealization (item 30). 
The change from baseline in BDI-II score will be analyzed in a Mixed Model Repeated 
Measures (MMRM) for the change from each baseline (P301 baseline and P303 baseline) 


Protocol: TNX-CY-P303                                                                                 Page 21 of 33 
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in separate, independent models. The model will include all participants in the safety 
population, and the dependent variable will be the observed change from each baseline at 
each post-randomization visit. Covariates in the model will include the fixed categorical 
effects of treatment, site, sex, current tobacco use status, presence of current MDE, visit 
and treatment 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 and placebo in the 
lead-in study at each time point. 
CGI-I score (which does not have baseline assessments) will use the same method, 
however, 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. 
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 
Binary data over time will be analyzed using a Cochran Mantel Haenszel (CMH) test 
stratified by presence of current major depressive episode. Participants with missing data 
will be analyzed as though they are non-responders. This will be reported for each 
endpoint. Differences in proportions along with two-sided 95% CIs will also be reported.  
Two-sided p-values for the test of no difference between the treatment groups will be 
provided. 
These endpoints will include: 
 Proportion of participants with a CGI-
. 
 Proportion of participants 
CAPS-5 score. 
 
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 


Protocol: TNX-CY-P303                                                                                 Page 22 of 33 
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 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. 
10.1 Adverse Events 
All AEs, newly-emergent adverse events (NEAEs), and SAEs will be coded using 
MedDRA, version 19.0. 
Newly emergent adverse events (NEAEs) are defined as any new AE that started after the 
in P303 had begun.  
An AE summary table will be presented for the following: 
 NEAEs by severity 
 NEAEs leading to study drug discontinuation  
 NEAEs by relationship 
 SAEs 
 Oral Cavity NEAEs 
 All AEs (including both NEAEs and ongoing AEs from the lead-in study) 
 All Oral Cavity AEs (including both Oral Cavity NEAEs and ongoing Oral Cavity 
AEs from the lead-in study 
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, oral cavity NEAEs, all AEs (including both NEAEs and ongoing AEs from the 
lead-in study), and all oral cavity AEs (including both oral cavity NEAEs and ongoing 
oral cavity NEAEs from the lead-in study). 
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. 
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. 
Adverse events of special interest pertaining to abuse potential will be analyzed 
separately by treatment group, SOC and preferred term, and displayed in tabular format. 
Terms to be included may be found in Appendix 3. 


Protocol: TNX-CY-P303                                                                                 Page 23 of 33 
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In the AE data listings, all AEs will be displayed. A separate by-patient listing of oral 
cavity AEs (including oral cavity AEs that were ongoing from P301) will be provided. 
AEs that are newly-emergent will be flagged in all AE listings. 
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 treatment group, 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 SAEs by treatment group, 
SOC, and preferred term will be prepared for the Safety population.  A data listing of 
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. 
10.2 Clinical Laboratory Evaluations 
Laboratory data include analyses for Chemistry and Hematology and will be summarized 
by treatment and visit for the Safety Population.  Descriptive summaries of actual values 
and changes from each baseline will be presented by study visit and each treatment 
group. 95% confidence intervals will be presented for change from each 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 each 
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.      


Protocol: TNX-CY-P303                                                                                 Page 24 of 33 
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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 
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 changes from each 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 each baseline. 
These summaries will be presented by treatment and 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 


Protocol: TNX-CY-P303                                                                                 Page 25 of 33 
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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 P303 as these should be 
captured entirely in P301.  Concomitant medications will be summarized by treatment 
group.  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.  
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 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 (  4 weeks (study day 
0 to 28), 4 to  8 (study day 29 to 56), 8 to  12 (study day 57 to 84) and > 12 weeks (study 
) 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.   


Protocol: TNX-CY-P303                                                                                 Page 26 of 33 
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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%, greater than 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-
assessment of potential abuse, misuse or diversion.  Tables will be created for higher 
level abuse-related MedDRA terms.  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. 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-P303                                                                                 Page 27 of 33 
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13. 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. 
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.  
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-P303                                                                                 Page 28 of 33 
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14. APPENDICES 
14.1 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. 
14.1.1 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-P303                                                                                 Page 29 of 33 
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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).  
14.1.2 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-P303                                                                                 Page 31 of 33 
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14.3 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


Protocol: TNX-CY-P303                                                                                 Page 32 of 33 
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Delusional perception
Depersonalisation
Depersonalisation/derealisation disorder
Derealisation
Disturbance in attention 
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


Protocol: TNX-CY-P303                                                                                 Page 33 of 33 
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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 
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