A 12-Week Open-Label Extension Study to Evaluate TNX-102 SL Taken Daily at Bedtime in Patients With PTSD
Phase: PHASE3
Conditions: PTSD
Sponsor: Tonix Pharmaceuticals, Inc.



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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 
from both baselines. 

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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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APPENDIX 3. AMRIX® PACKAGE INSERT (DATED MAY 2016) 
 

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