Clinical trial NCT03062540
Conditions: PTSD
Keywords: PTSD Military-related PTSD
Sponsor: Tonix Pharmaceuticals, Inc.
Start date: 2017-03-27; Completion date: 2018-07-27
Enrollment: 358 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 12-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study that will investigate the efficacy and safety of 5.6 mg TNX-102 SL (2 x 2.8 mg tablets)-a sublingual formulation of cyclobenzaprine. Following successful screening and randomization, eligible patients will have a telephonic visit at week 2 and then return regularly to the study clinic for monthly visits for assessments of efficacy and safety.

Detailed description:

Arms: arm 1: 2 x TNX-102 SL, 2.8 mg Tablets taken sublingually each day at bedtime for 12 weeks. arm 2: 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks.
Interventions: intervention 1: TNX-102 SL intervention 2: Placebo SL Tablet
Intervention descriptions: intervention 1: Patients will take 2 tablets of randomly assigned study drug sublingually each day at bedtime starting on Day 0 for 12 weeks intervention 2: Patients will take 2 tablets of randomly assigned study drug sublingually each day at bedtime starting on Day 0 for 12 weeks

Protocol documents:
Prot_000.pdf: 


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INVESTIGATOR’S AGREEMENT 
I have read the TNX-CY-P301 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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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 Phase 3, Double-Blind, Randomized, Multicenter, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of TNX-102 SL Taken Daily at Bedtime in Patients with Military-Related PTSD 
(Protocol No. TNX-CY-P301)  
Study center(s): Approximately 45 centers in the United States 
Study center(s) participating in the post-study pharmacogenomic assessment: 5 of the 45 centers 
that participated in the randomized, double-blind, placebo-controlled protocol 
Studied period (years): 1.5 
Estimated date first patient enrolled: February 2017 
Estimated date last patient completed: January 2019 
Studied period (months) for the post-study 
pharmacogenomic assessment: 3 
Estimated date first patient enrolled: November 2019 
Estimated date last patient completed: January 2020 
 
Phase of development: 3 
 
Objectives: 
Primary: 
To evaluate the efficacy of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) in the treatment of 
military-related posttraumatic stress disorder (PTSD) 
Secondary: 
To evaluate the safety of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) in the treatment of 
military-related posttraumatic stress disorder (PTSD) 
Methodology:  
This is a 12-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study that 
will investigate the efficacy and safety of 5.6 mg TNX-102 SL (2 x 2.8 mg tablets)—a sublingual 
formulation of cyclobenzaprine.  Following successful screening and randomization, eligible patients 
will have a telephonic visit at week 2 and then return regularly to the study clinic for monthly visits 
for assessments of efficacy and safety. 
There will be a total of 6 study visits over approximately 13-17 weeks of study participation, 
including Screening (Visit 1), Randomization (Day 0, Visit 2), a phone visit after 2 weeks of 
treatment and in-clinic visits after 4, 8, and 12 weeks of treatment.  A total of approximately 550 
patients will be randomized in a 1:1 ratio to placebo or TNX-102 SL 5.6 mg (2 x 2.8 mg tablets). 
Approximately 15 patients that successfully completed the TNX-CY-P301 study will be invited back 
to participate in a post-study pharmacogenomic assessment. 


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Number of patients (planned):  
Approximately 550 patients will be randomized.  Randomized patients who withdraw will not be 
replaced. 
Approximately 15 patients will be invited to participate in a post-study pharmacogenomic assessment. 
Diagnosis and main criteria for inclusion:  
Inclusion criteria (assessed at Screening Visit 1): 
1. Male or female between 18 and 75 years of age, inclusive, with military service (defined as 
active duty military, National Guard, reservist, veteran or military contractor).  Identification 
confirming military service will be checked prior to randomization; medical monitor approval 
will be required for potential patients unable to provide evidence of prior service. 
2. Diagnosed with current PTSD as determined by the Clinician-Administered PTSD Scale 
(CAPS-5) for Diagnostic and Statistical Manual of Mental Disorders-Version 5 (DSM-5) and 
of sufficient symptom severity, defined as all of the following at Screening Visit 1 using the 
Diagnostic version (1-month recall): 
a. The A criterion is 1=YES, and 
b. At least ONE item of the B criterion items must have a score of ≥2, and 
c. At least ONE item of the C criterion items must have a score of ≥2, and 
d. At least TWO items of the D criterion items must have a score of ≥2, and 
e. At least TWO items of the E criterion items must have a score of ≥2, and  
f. The F item 22 criterion is 1=YES (≥1 month duration of symptoms) 
g. At least ONE item of the G items must have a score of ≥2, and 
h. The total CAPS-5 score (of items 1 through 20 is) ≥33. 
3. Index trauma(s) resulting in PTSD must meet the following: 
a. DSM-5 criterion A for PTSD as described in the CAPS-5 and Criterion A – Assessment 
Form (CA-AF), and 
b. Must have occurred in 2001 or later, and 
c. Must be military service-related (either occurrence during military service, including 
during National Guard service or as reservist), and 
d. Must have occurred when the patient was ≥18 years of age.  
4. Willing and able to withdraw and refrain from opioids for the course of the study. 
5. Willing to refrain from use of all other formulations of cyclobenzaprine for the course of the 
study. 
6. Willing and able to refrain from antidepressants, antipsychotics, mood stabilizers, 
anticonvulsants, benzodiazepines, non-benzodiazepine hypnotics, buspirone, stimulants (e.g. 
amphetamines, methylphenidate, modafinil, armodafinil), prazosin and trazodone for the 
course of the study. 
7. Capable of reading and understanding English and able to provide written informed consent 
to participate.  
8. If female, either not of childbearing potential (defined as postmenopausal for at least one year 
or surgically sterile [e.g., bilateral tubal ligation; bilateral oophorectomy; hysterectomy, etc.]) 


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or practicing one of the following medically acceptable methods of birth control throughout 
the study: 
a. Hormonal methods such as oral, implantable, injectable, or transdermal contraceptives for 
a minimum of one full cycle (based on the patient’s usual menstrual cycle period) before 
study drug administration; 
b. Intrauterine device (IUD); 
c. Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal 
jellies or cream); 
d. In sexually-exclusive relationship with vasectomized male partner, or in same-sex 
relationship with no plans for artificial or other forms of insemination. 
9. Willing and able to comply with all protocol-specified requirements. 
10. If patient has received trauma-focused treatment (e.g., cognitive behavioral therapy for 
PTSD, prolonged exposure therapy, desensitization therapy, etc.) must have been completed 
at least three months prior to the Baseline visit, and there can be no plans to initiate this type 
of therapy during study.  General psychotherapy that was in process at time of Screening may 
be continued during the trial, but no new initiation of treatment is allowed during the trial 
after enrollment. 
11. Separate written, signed informed consent will be required if the patient is to participate in the  
post-study pharmacogenomic assessment. To be eligible to participate in the 
pharmacogenomic assessment, the patient must have been randomized, had at least one post-
baseline CAPS-5 assessment, and received active study drug in the TNX-CY-P301 study.  
Exclusion Criteria 
1. Increased risk of suicide on the basis of the investigator’s judgment and/or the results of the 
Mini International Neuropsychiatric Interview, Version 7.0.2 (M.I.N.I. 7.0.2) conducted at 
Screening and the Columbia Suicide Severity Rating Scale (C-SSRS) conducted at Screening 
and/or Baseline.  Any of the following will be exclusionary: 
a. High suicidality based on a M.I.N.I. Module B score ≥ 17 (Screening); or, 
b. Patient answers YES to either M.I.N.I. question B10 or B11 (Screening); or, 
c. Patient meets criteria for CURRENT Suicidal Behavior Disorder on the M.I.N.I 
(Screening); or, 
d. C-SSRS Type 4 or Type 5 ideation within 6 months of Screening or at the Baseline visit; 
or, 
e. Any suicidal behavior in the past 12 months as identified by the C-SSRS at Screening or 
Baseline. 
2. Increased risk of suicide, based on the investigator’s judgment that is of a severity that is not 
appropriate for outpatient management, or that warrants additional therapy excluded by the 
protocol. 
3. Significant (e.g., moderate or severe) comorbid traumatic brain injury (TBI) by history.  
Based on past history and investigator’s judgment, patients with mild TBI are eligible. 
4. Evidence of severe depression at screening or baseline (Visits 1 or 2) based on the 
investigator’s judgment and collaborative pre-randomization review by the investigator and 
medical monitor(s) of the patient’s psychiatric history, presenting symptomatology, M.I.N.I. 


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7.0.2 (including Major Depressive Episode and Suicidality modules), C-SSRS, CAPS-5, and 
BDI-II assessments. 
5. Clinically significant laboratory abnormalities based on screening laboratory tests and/or 
medical history in the investigator’s opinion, including a Thyroid Stimulating Hormone 
(TSH) level >1.5 times the upper limit of normal and aspartate aminotransferase (AST) 
and/or alanine aminotransferase (ALT) > 3 times the upper limit of normal (if persistent upon 
repeat).  Patients with treated thyroid conditions and TSH levels < 1.5 times the upper limit of 
normal will be eligible to participate in the study. 
6. Diagnosed with clinically significant cardiac disease (e.g., significant arrhythmia or heart 
block, heart failure, or recent myocardial infarction [within the past 2 years]) or QTcF >450 
msec (male) or >470 msec (female) on the screening electrocardiogram (ECG). 
7. Current evidence of human immunodeficiency virus (HIV) infection based on screening 
laboratory results or medical history, or clinically significant hepatitis B or C infection as 
defined by current treatment or liver function tests (e.g., aspartate aminotransferase [AST] or 
alanine aminotransferase [ALT] > 3 times the upper limits of normal). 
8. Use of antidepressant medication within 2 months of baseline, with the exception of 
trazodone at doses ≤ 150 mg per day or tricyclic antidepressants at doses ≤25 mg per day, 
which instead require a 1-week drug-free interval prior to the Baseline visit. 
9. Unable to successfully wash out of the following medications during screening, or in whom 
washout is medically inadvisable: anticonvulsants, mood stabilizers, anti-psychotic agents, 
opioids, benzodiazepines, non-benzodiazepine hypnotics (zolpidem; eszopiclone, zaleplon), 
buspirone, trazodone, stimulants (e.g., amphetamine mixed salts, methylphenidate, 
lisdexamphetamine, dextroamphetamine, modafanil, armodafanil), atomoxetine,  or any 
medication known to be a potent (strong) cytochrome P450 subtype 3A4 (CYP3A4) inhibitor, 
or St. John’s wort.  Note:  Use of caffeine and/or nicotine is permitted. 
10. Unable to successfully wash out of alpha-adrenergic antagonists and/or agonists (e.g., 
prazosin, terazosin, doxazosin, tamsulosin, silodosin, tizanidine, clonidine, guanfacine) or 
when washout is medically inadvisable. 
11. Positive results for illegal or abused substances other than cannabis at Screening or Baseline 
or history of alcohol/substance use disorder during the preceding 6 months as defined by the 
screening M.I.N.I. 7.0.2.  Patients who utilize alcohol/cannabis but do not meet criteria for 
alcohol/substance use disorder are otherwise suitable for the study provided that, in the 
judgment of the Investigator, this usage will not interfere with the patient’s ability to 
complete the study or provide reliable data. 
12. Any clinically significant, uncontrolled, or unstable medical or surgical condition that could 
affect a patient’s ability to participate in the study or potentially compromise a patient’s well-
being during the study, including patients with a history of untreated or uncontrolled 
angle-closure glaucoma.   
13. Diagnosis of DSM-5-defined bipolar disorder I, II or unspecified, schizophrenia, 
schizoaffective disorder, obsessive-compulsive disorder, major depressive disorder (MDD) 


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with psychotic features, other psychotic disorder, or antisocial personality disorder as 
confirmed by the M.I.N.I. Version 7.0.2. 
14. History within the past 2 years of violent behavior unrelated to military duties or associated 
work. 
15. Anticipated need for surgery that might confound results or interfere with patient’s ability to 
comply with the protocol. 
16. Female patients who are pregnant or lactating. 
17. History of serotonin syndrome, severe allergic reaction or bronchospasm or known 
hypersensitivity to cyclobenzaprine or the excipients in TNX-102 SL or placebo 
formulations. 
18. Seizure disorder other than history of childhood febrile seizures. 
19. Current sleep apnea not well controlled by Continuous Positive Airway Pressure (CPAP) or 
oral (mouthpiece) devices.  Patients with mild obstructive sleep apnea or those well 
controlled by CPAP or oral (mouthpiece) devices are allowed at the discretion of the 
investigator. 
20. Patients with a body mass index (BMI) > 45. 
21. Has received any other investigational drug within 30 days before Screening or has taken 
cyclobenzaprine within 21 days of the Randomization visit. 
22. Previous participation in any other study with TNX-102 SL. 
23. Any existing oral medical or dental condition, or tongue piercings, that could potentially 
interfere with sublingual administration of study drug, or history of severe or unexplained 
oral or oropharyngeal swelling or edema. 
24. Family member of investigative staff. 
25. In the process of litigating for compensation for a psychiatric disorder.  Patients who are in 
the process of applying for VA benefits or who have a settled claim are eligible. 
Randomization Criteria:  All of the following must be met before the patient is eligible for 
randomization at Visit 2: 
1. Patient continues to meet all inclusion and exclusion criteria, including urine and blood test 
results, and 
2. Visit 2 total CAPS-5 score ≥ 33 (“Symptom Severity” version using 1-week recall), and 
3. At Visit 2, patient is not severely depressed (based on the investigator’s judgment and Visit 2 
C-SSRS, CAPS-5, and BDI-II, and considering the pre-randomization collaborative review by 
the investigator and medical monitor(s) of the patient’s Visit 1 psychiatric history, presenting 
symptomatology, M.I.N.I. 7.0.2, C-SSRS, CAPS-5, and BDI-II assessments), and 
4. No active suicidal intent or plan, based on Investigator’s judgment, and Visit 2 C-SSRS 
responses (e.g., no C-SSRS Type 4-5 ideation or suicidal behavior since Visit 1). 
 


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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: 
Name: Placebo 
Dose, route, frequency: 2 placebo tablets taken simultaneously and sublingually (under the tongue) 
each day at bedtime starting on Day 0 for 12 weeks. 
Criteria for evaluation: 
Primary Efficacy Endpoint: 
• 
The mean change from baseline (Visit 2) in the Total CAPS-5 score after 12 weeks of 
treatment evaluated at Visit 6. 
Secondary Efficacy Endpoints: The first two secondary efficacy endpoints listed below are 
considered key secondary endpoints and will be tested in that order: 
• 
CGI-I score (analyzed as a continuous variable) after 12 weeks of treatment. 
• 
Change from baseline in the SDS total score after 12 weeks of treatment. 
A fixed sequence procedure will be applied to the key secondary efficacy endpoints to adjust for 
multiplicity and to control for overall type I error. 
 
Other Secondary Efficacy Endpoints: 
• 
Change from baseline in patients’ quality of sleep using the PROMIS Sleep Disturbance 
scale after 12 weeks of treatment. 
• 
Change from baseline in the disruption of work/school activities assessed using the SDS 
after 12 weeks of treatment. 
• 
Change from baseline in disruption of social life/ leisure activities assessed using the SDS 
after 12 weeks of treatment. 
• 
Change from Baseline in the disruption of family life/home responsibilities assessed 
using the SDS after 12 weeks of treatment. 
• 
Change from baseline in CAPS-5 Arousal and Reactivity (Criterion E) score after 12 
weeks of treatment. 
• 
Change from baseline in CAPS-5 Intrusion symptoms (Criterion B) score after 12 weeks 
of treatment. 
• 
Change from baseline in CAPS-5 Persistent Avoidance (Criterion C) score after 12 weeks 
of treatment. 
• 
 Change from baseline in CAPS-5 Negative Cognition and Mood (Criterion D) score after 
12 weeks of treatment. 
• 
Change from baseline in CAPS-5 Sleep Disturbance (item E-6) score after 12 weeks of 
treatment. 
• 
Change from baseline in CAPS-5 Exaggerated Startle (item E-4) score after 12 weeks of 
treatment. 
• 
PGIC score after 12 weeks of treatment. 
• 
Proportion of patients with a PGIC score of “much improved” or “very much improved” 
after 12 weeks of treatment 


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• 
Proportion of patients with a treatment response on the CGI-I defined as a CGI-I score of 
“much improved” or “very much improved” after 12 weeks of treatment. 
• 
Proportion of patients with a Total CAPS-5 score of 0 –10 (asymptomatic/few symptoms) 
after 12 weeks of treatment. 
• 
Proportion of patients with a Total CAPS-5 score of 0-22 (asymptomatic or mild 
PTSD/subthreshold) after 12 weeks of treatment. 
• 
Proportion of patients with Response, defined as a ≥ 10-point improvement from baseline 
in Total CAPS-5 score after 12 weeks of treatment. 
• 
Proportion of patients with Loss of Diagnosis, defined as Response AND no longer 
meeting DSM-5 symptom criteria in any one or more of the four clusters (B, C, D, E) 
after 12 weeks of treatment. 
• 
Proportion of patients in Remission, defined as Loss of Diagnosis AND Total CAPS-5 
score ≤ 10 after 12 weeks of treatment. 
• 
Proportion of patients achieving sustained Remission, defined as Loss of Diagnosis AND 
Total CAPS-5 score ≤ 10 after both 8 weeks AND 12 weeks of treatment. 
• 
Proportion of patients with a ≥50% improvement from baseline in Total CAPS-5 score 
after 12 weeks of treatment. 
• 
Change from baseline in BDI-II score after 12 weeks of treatment. 
• 
Change from baseline in CAPS-5 Reckless or Self-Destructive Behavior (item E-2) score 
after 12 weeks of treatment.  
 
 
Exploratory Endpoints:  Any exploratory endpoints will be delineated in the SAP. 
 
Safety 
Safety will be assessed by: 
• 
Adverse events (AE) and serious AEs (SAEs) throughout the entire duration of the study, 
including detailed assessment of AEs involving the oral cavity 
• 
Changes from baseline in clinical laboratory test results 
• 
Changes from baseline in vital signs and weight 
• 
Change from baseline in BDI-II 
• 
Changes from baseline indicative of increased suicidal ideation or behavior as assessed 
by the Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
Changes from baseline in patient-rated Changes in Sexual Functioning Questionnaire 
Short-Form (CSFQ-14) 
• 
Changes from baseline in patient-rated morning sedation as assessed by the Morning 
Treatment-Related Sedation Score (MTRSS) 
 
Statistical methods: 
Analysis Populations 
• 
Safety Population (SAFETY): All patients who receive at least one dose of 
investigational product, analyzed as treated. 
• 
Modified Intent-to-Treat Population (mITT):  All randomized patients who have at least a 
baseline and one post-baseline CAPS-5 assessment, analyzed as randomized. 
 






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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 ...............13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Sleep and PTSD ..........................................................................................................24 
5.1.1. 
Brief Summary of Prior Clinical Experience and Dose Rationale .............................25 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................29 
6.1. 
Primary Objective .......................................................................................................29 
6.2. 
Secondary Objectives .................................................................................................29 
7. 
INVESTIGATIONAL PLAN .....................................................................................29 
7.1. 
Overall Study Design ..................................................................................................29 
7.2. 
Number of Patients and Treatment Assignment .........................................................30 
7.3. 
Study Endpoints ..........................................................................................................30 
7.3.1. 
Primary efficacy endpoint ...........................................................................................30 
7.3.2. 
Secondary efficacy endpoints .....................................................................................31 
7.3.2.1. 
Key Secondary Efficacy Endpoints ............................................................................31 
7.3.2.2. 
Other Secondary Efficacy Endpoints ..........................................................................31 
7.3.3. 
Exploratory efficacy endpoints ...................................................................................32 
7.3.4. 
Safety ..........................................................................................................................32 
7.4. 
Efforts to Minimize Missing Data ..............................................................................33 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................33 
8.1. 
Informed Consent .......................................................................................................33 
8.2. 
Inclusion Criteria ........................................................................................................34 
8.3. 
Exclusion Criteria .......................................................................................................35 
8.4. 
Randomization Criteria ...............................................................................................37 
8.5. 
Prior and Concomitant Medications ...........................................................................38 
8.5.1. 
Allowed Concomitant Medications ............................................................................39 
8.6. 
Withdrawal Criteria ....................................................................................................39 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................39 
9.1. 
Study Drug Packaging, and Labeling and Storage .....................................................39 
9.2. 
Dosing Instructions .....................................................................................................40 
9.3. 
Dispensing Instructions ..............................................................................................40 
9.4. 
Release of Clinical Study Supplies to the Investigator ...............................................41 
9.5. 
Study Drug Accountability and Reconciliation ..........................................................41 
10. 
STUDY VISITS AND PROCEDURES .....................................................................42 
10.1. 
Visit 1 (Screening: Day -35 to -7) ..............................................................................42 
10.1.1. 
Informed Consent .......................................................................................................42 
10.1.2. 
Screening Overview ....................................................................................................42 
10.1.3. 
Patient Numbering ......................................................................................................42 
10.1.4. 
Screening and Assessments/Procedures .....................................................................42 
10.2. 
Visit 2 (Baseline: Day 0) ............................................................................................44 
10.2.1. 
Pre-Randomization Assessments ................................................................................44 
10.2.2. 
Randomization Criteria ...............................................................................................44 
10.3. 
Visit 3 (Telephone Visit: Day 14) ..............................................................................45 
10.4. 
Visit 4 and 5 (Weeks 4 through 8) ..............................................................................45 
10.5. 
Visit 6 (Week 12) ........................................................................................................46 
10.5.1. 
Early Termination (ET) ..............................................................................................47 
10.5.2. 
Unscheduled Visits .....................................................................................................49 
11. 
STUDY ASSESSMENTS ..........................................................................................50 
11.1. 
Screening Assessments ...............................................................................................50 
11.1.1. 
Psychiatric and Medical History .................................................................................50 
11.2. 
Efficacy Assessments .................................................................................................50 
11.2.1. 
Clinician-Administered PTSD Scale (CAPS-5) .........................................................51 
11.2.2. 
Beck Depression Inventory (BDI-II) ..........................................................................52 
11.2.3. 
Clinical Global Impression of Improvement (CGI-I) .................................................52 
11.2.3.1. 
CGI-I Assessments at Weeks 4, 8, and 12 ..................................................................53 
11.2.4. 
Patient Global Impression of Change (PGIC) ............................................................53 
11.2.5. 
PROMIS Sleep (short form) Scale .............................................................................53 
11.2.6. 
Sheehan Disability Scale (SDS) .................................................................................53 
11.3. 
Safety Parameters .......................................................................................................54 


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11.3.1. 
Adverse Events (AEs) .................................................................................................54 
11.3.2. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................54 
11.3.3. 
Safety Planning Intervention (SPI) .............................................................................55 
11.3.4. 
Physical Examination .................................................................................................55 
11.3.5. 
Visual Examination of Oral Cavity ............................................................................55 
11.3.6. 
Vital Signs, Height and Weight ..................................................................................55 
11.3.7. 
Electrocardiogram (ECG) ...........................................................................................56 
11.3.8. 
Clinical Laboratory Assessments ...............................................................................56 
11.3.9. 
Assessment of Changes in Sexual Function: Changes in Sexual Functioning 
Questionnaire Short-Form (CSFQ-14) .......................................................................57 
11.3.10. 
Assessment of Sedation:  Morning Treatment-Related Sedation Score 
(MTRSS).....................................................................................................................58 
12. 
DEFINITIONS, RECORDING, AND REPORTING OF ADVERSE 
EVENTS .....................................................................................................................58 
12.1. 
Definition of Adverse Events .....................................................................................58 
12.2. 
Adverse Event Recording ...........................................................................................59 
12.2.1. 
Coding the Adverse Event ..........................................................................................59 
12.2.2. 
Severity of Adverse Event ..........................................................................................59 
12.2.3. 
Relationship of Adverse Events to Study Drug ..........................................................59 
12.3. 
Serious Adverse Events (SAEs) and Serious Adverse Drug Reactions .....................60 
12.4. 
Pregnancy ...................................................................................................................61 
13. 
STATISTICS ..............................................................................................................62 
13.1. 
Populations for Analysis .............................................................................................62 
13.2. 
Estimate of Sample Size .............................................................................................62 
13.3. 
Assessment of Demographic and Baseline Characteristics ........................................63 
13.4. 
Efficacy Analysis ........................................................................................................63 
13.4.1. 
Efficacy Endpoints ......................................................................................................63 
13.4.2. 
Primary Efficacy Analysis ..........................................................................................64 
13.4.3. 
Secondary Efficacy Analyses .....................................................................................65 
13.4.4. 
Exploratory Analyses ..................................................................................................65 
13.5. 
Safety Analyses ..........................................................................................................65 
13.6. 
Interim Analyses .........................................................................................................66 


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14. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY .................................................................................67 
14.1. 
Protocol Modifications and Deviations ......................................................................67 
14.2. 
Study Termination ......................................................................................................67 
15. 
ETHICAL CONSIDERATIONS................................................................................67 
15.1. 
Ethical Conduct of the Study ......................................................................................67 
15.2. 
Ethics Committee/Institutional Review Board (EC/IRB) Review .............................68 
15.3. 
Written Informed Consent ..........................................................................................68 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................69 
16.1. 
Maintaining Privacy and Confidentiality....................................................................69 
16.2. 
Maintaining Essential Clinical Documents ................................................................69 
16.3. 
Data Handling .............................................................................................................70 
16.4. 
Case Report Forms (CRFs) .........................................................................................70 
16.5. 
Screening Records ......................................................................................................70 
16.6. 
Clinical Laboratory Certification ................................................................................71 
16.7. 
Site Monitoring and Tonix’s Right to Review Records .............................................71 
16.8. 
Audits and Inspections ................................................................................................71 
17. 
CONFIDENTIALITY ................................................................................................72 
17.1. 
Protection of Patient Anonymity ................................................................................72 
17.2. 
Confidentiality of Study Information .........................................................................72 
17.3. 
Publication of Data and Protection of Trade Secrets ..................................................72 
18. 
LIST OF REFERENCES ............................................................................................74 
19. 
APPENDICES ............................................................................................................79 
APPENDIX 1. STUDY DESIGN AND SCHEDULE OF ASSESSMENTS .............................79 
APPENDIX 2. LIST OF CYP3A INHIBITORS ........................................................................82 
APPENDIX 3. AMRIX® PACKAGE INSERT (DATED MAY 2016) ......................................83 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Clinical Laboratory Assessments ...............................................................................57 
Table 3: 
Medical Monitoring Contact Information ..................................................................61 


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LIST OF FIGURES 
Figure 1: 
CAPS-5 Mean Change from Baseline Over 12 Weeks of Study in ≥33 
Subset ..........................................................................................................................27 
 


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4. 
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 
ANCOVA 
Analysis of covariance 
AR 
α2-adrenoreceptors 
AST 
Aspartate Aminotransferase 
BDI-II 
Beck Depression Inventory–II 
BMI 
Body Mass Index 
BOCF 
Baseline observation carried forward 
BUN 
Blood urea nitrogen 
CAPS-5 
Clinician Administered PTSD Scale (for DSM-5) 
CA-AF 
Criterion A – Assessment Form 
CBP 
Cyclobenzaprine 
CSFQ-14 
Changes in Sexual Functioning Questionnaire Short Form 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression- Improvement from Initiation of Treatment 
CI 
Confidence Interval 
CMH 
Cochran–Mantel–Haenszel 
CNS 
Central Nervous System 
CoC 
Certificates of Confidentiality 
CPAP 
Continuous Positive Airway Pressure 
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 


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Abbreviation or 
Specialist Term 
Explanation 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HCl 
Hydrochloride 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV1 
Human immunodeficiency virus type 1 
HIV2 
Human immunodeficiency virus type 2 
i.e. 
id est (that is) 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IR 
Immediate-release 
ISAP 
Interim Statistical Analysis Plan 
IUD 
Intrauterine device 
IWR 
Interactive Web Response 
LEC-5 
Life Events Checklist for DSM-5 
LOCF 
Last observation carried forward 
M.I.N.I. 
Mini International Neuropsychiatric Interview 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
mCPP 
meta-chlorophenylpiperazine  
MCV 
Mean corpuscular volume 
MDD 
Major Depressive Disorder 


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Abbreviation or 
Specialist Term 
Explanation 
MDE 
Major Depressive Episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram(s) 
MI 
Multiple imputation 
mITT  
Modified Intent-to-Treat 
MMRM 
Mixed Model Repeated Measures 
msec 
Millisecond(s) 
MTRSS 
Morning Treatment-Related Sedation Scale 
N, n 
Number (of patients) 
NA 
Not applicable 
NDA 
New Drug Application 
NREM 
Non-rapid eye movement 
OEF 
Operation Enduring Freedom 
OIF 
Operation Iraqi Freedom 
OND 
Operation New Dawn 
PCL 
PTSD Checklist 
PGIC 
Patient Global Impression of Change (Since Baseline) Scale 
PI 
Principal Investigator 
PO 
per os (by mouth) 
PRN 
pro re nata (as needed) 
PROMIS 
Patient-Reported Outcome Measurement Information System 
PTSD 
Post-Traumatic Stress Disorder 
QTcF 
QT corrected for heart rate using Fridericia’s formula 
RBC 
Red blood cell 
REM 
Rapid eye movement 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SDS 
Sheehan Disability Scale 


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Abbreviation or 
Specialist Term 
Explanation 
SL 
Sublingual 
SOP 
Standard Operating Procedures 
SPI 
Safety Planning Intervention 
SWS 
Slow wave sleep 
TBI 
Traumatic brain injury 
TEAE 
Treatment Emergent Adverse Event 
TNX-102 SL  
Cyclobenzaprine HCl sublingual tablets 
TSH 
Thyroid Stimulating Hormone 
US 
United States 
VA 
Veteran’s Administration 
WBC 
White blood count 
WHO 
World Health Organization 
 


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5. 
INTRODUCTION 
TNX-102 SL is a tablet for sublingual administration containing cyclobenzaprine HCl [3-(5H-
dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride].  TNX-102 SL 
2.8 mg tablets are under development by Tonix Pharmaceuticals, Inc. (Tonix) as a treatment for 
posttraumatic stress disorder (PTSD). 
The active ingredient in TNX-102 SL, cyclobenzaprine HCl (CBP), has been approved for use in 
the United States (US) since 1977, originally as FLEXERIL® 10-mg oral tablets indicated as an 
adjunct to rest and physical therapy for the relief of muscle spasm associated with acute, painful 
musculoskeletal conditions.  The usual dose for this indication is 30 mg or 15 mg per day taken 
as 10 mg TID or 5 mg TID, respectively.  The FLEXERIL brand of immediate-release (IR) 
cyclobenzaprine tablets has been discontinued since May 2013.  Generic cyclobenzaprine is 
available and marketed in a variety of strengths including 5-, 7.5- and 10-mg IR tablets. 
AMRIX® (AMRIX® Prescribing Information, 2016), an extended-release capsule of 
cyclobenzaprine was approved in 2007 in the US as a New Drug Applications (NDA) and is 
currently available in 15- and 30-mg, taken once a day for the same indication as FLEXERIL in 
the US.  Both FLEXERIL and AMRIX are indicated for 2-3 weeks use only.  No 
cyclobenzaprine product has been approved for use in PTSD by Food and Drug Administration 
(FDA), Health Canada, or in any other country. 
As its primary pharmacologic action in relief of muscle spasm, cyclobenzaprine has been shown 
to decrease skeletal muscle hyperactivity in several animal models through central mechanisms 
involving blockade of either α2-adrenoreceptors (Barnes et al, 1980) (AR) or serotoninergic 5-
HT2A receptors (Kobayashi et al, 1996; Honda et al, 2003).  Cyclobenzaprine acts primarily in 
the central nervous system (CNS) at the brain stem rather than at the spinal cord level, and does 
not act directly at the neuromuscular junction or directly on skeletal muscle. 
In addition to these primary pharmacologic actions, cyclobenzaprine has been observed to 
increase restorative sleep in fibromyalgia patients, which was correlated with improvement in 
daytime symptoms in a proof-of-concept study conducted by Vela Pharmaceuticals (Protocol No. 
VPI CY 0001.1) (Moldofsky et al, 2011) using low dose cyclobenzaprine (TNX-102 capsules).  
The rationale for testing cyclobenzaprine as a treatment for PTSD is based on known effects of 
cyclobenzaprine on CNS receptors and, in part, on the relationship of fibromyalgia and PTSD to 
disturbed and non-restorative sleep. 
PTSD is characterized by symptom clusters that include re-experiencing (intrusion) symptoms, 
avoidant behaviors, negative mood and cognitions, and heightened arousal and reactivity, the 
array of which develops and persists following exposure to a severely traumatic event.  It is well 
established that sleep disturbances are common among individuals with PTSD that has 
developed in response to combat traumas (Mellman et al, 1995; Pietrzak et al, 2010; Neylan et 
al, 1998) and sexual assault (Steine et al, 2012), including military sexual trauma (Kelly et al, 
2011).  Among military personnel returning from OEF/OIF/OND deployments to Afghanistan 
and Iraq, sleep disturbances are considered the most frequent and severe of the PTSD symptoms 
(McLay et al, 2010).  Sleep disturbances are considered core features of PTSD and are 
components of two of the main symptom clusters of PTSD including distressing dreams (re-
experiencing cluster) and insomnia and restless sleep (hyperarousal cluster) (Krakow et al, 2001; 
Spoormaker et al, 2008).  Problems with sleep are not only thought to significantly exacerbate 


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daytime symptoms of PTSD but also increase the likelihood of comorbid complications such as 
depression and substance use disorders as well as suicidal behaviors (Krakow et al, 2002; 
Saladin et al, 1995; Krakow et al, 2000), a particularly critical problem in PTSD (Oquendo et al, 
2003; Sareen et al, 2005).  Moreover, because of a direct relationship between sleep disturbance 
in PTSD and suicidal ideation, it is suggested that targeting sleep disturbance may help prevent 
suicidal behaviors in PTSD (Betts et al, 2013). 
A growing body of evidence suggests that sleep disruption plays an important causal role in the 
pathogenesis of PTSD (Koren et al, 2002; Mellman et al, 2002; McLay et al, 2010; Wright et al, 
2011).  Moreover, sleep disturbance is a frequent residual complaint after successful PTSD 
treatment, a finding that applies to both psychological and pharmacological treatment 
(Spoormaker et al, 2008).  Evidence is now emerging that pharmacological targeting of sleep 
disturbance in PTSD, in which self-reported and polysomnographic improvement in sleep 
parameters is achieved, can account for over 90% of the variance in improvement in PTSD 
severity ratings and work/school function (Krystal et al, 2013). 
Understanding of PTSD pathophysiology has been greatly advanced due to heuristic models of 
trauma based on animal work on fear conditioning and extinction (Yehuda & LeDoux, 2007; 
Maren et al, 2013).  Human studies of fear memory and stress responsiveness have highlighted 
the potential role of sleep, particularly rapid eye movement (REM) sleep, in affective and 
memory processes (Pace-Schott et al, 2015; Yoo et al, 2007; Pace-Schott et al, 2009).  There is 
evidence for the hypothesis that sleep disturbances play a critical role in PTSD by compromising 
sleep-dependent affective and memory processing that may be key for recovery from PTSD 
(Yehuda & LeDoux, 2007). 
5.1. 
Sleep and PTSD 
Subjective sleep disturbance, characterized by non-restorative sleep, frequent awakenings and 
distressing dreams and nightmares related to the trauma, is a core feature of PTSD (Spoormaker 
et al, 2008).  Clinical observations focusing on the nature of sleep complaints suggest 
dysregulation in both REM and non-rapid eye movement (NREM) sleep in PTSD (Woodward et 
al, 2000; Germain et al, 2013).  Meta-analysis of polysomnography (PSG) studies in both 
military veterans and adult civilians suggest modest indices of sleep disruption in PTSD using 
these traditional measures, with greater stage 1 (light) sleep, reduced slow wave sleep (SWS), 
and greater REM density compared with individuals without PTSD (Kobayashi et al, 2007). 
Quantitative EEG, in which high frequency beta and gamma activity are considered indices of 
central arousal during sleep, has indicated both greater beta activity during NREM and lesser 
beta activity during REM sleep in PTSD, as well as disturbances in delta activity, and heart rate 
differences between REM and NREM related to the amount of REM sleep (Woodward et al, 
2002; Neylan et al, 2003; Halász et al, 2004; Woodward et al, 2000).  Such changes are 
consistent with the pathophysiology of PTSD, which involves hypervigilance and exaggerated 
responses to both external and internal stimuli, and which are putatively indicative of heightened 
nocturnal sympathetic noradrenergic activity (Berridge et al, 2012; Breslau et al, 2005; Capaldi 
et al, 2011). 
A recent evaluation of treatment algorithms for PTSD found that addressing fragmented sleep 
and nightmares consistently improves all symptom domains in PTSD, such that targeting sleep-
related symptoms has been recommended as an initial step for treatment of all patients with 










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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To evaluate the efficacy of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) in the 
treatment of military-related PTSD. 
6.2. 
Secondary Objectives 
To evaluate the safety of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) in the treatment 
of military-related PTSD. 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3, 12-week, randomized, multicenter, double-blind, placebo-controlled, fixed 
dose study that will investigate the efficacy and safety of TNX-102 SL 5.6 mg (2 x 2.8 mg 
tablets) taken daily at bedtime for the management of military-related PTSD.  This study is to be 
conducted at approximately 45 investigational sites in the United States. 
The total duration of this study over 6 visits will be approximately 13-17 weeks, with 12 weeks 
of treatment duration and a variable length of screening.  This study will consist of a Screening 
visit (Visit 1, Days −35 to −8), Randomization visit (Visit 2, Day 0), telephone visit (Visit 3, 
Week 2) and three monthly in-clinic visits (Visits 4, 5 and 6 at Weeks 4, 8, and 12). 
Eligible patients who provide written informed consent to participate will have study 
assessments performed at Screening, including counseling regarding any required washout and 
instructions to refrain from use of excluded medications throughout the study. 
The length of the pre-randomization screening period is variable (7 to 35 days) in order to 
accomplish wash-out of previous medications, where appropriate, and allow for return of clinical 
laboratory results necessary to confirm eligibility.  At Visit 2, patients will return to the site for 
additional baseline assessments and randomization (Day 0), when, if they meet all study 
randomization criteria, they will be randomly assigned in a 1:1 ratio to receive placebo or TNX-
102 SL 5.6 mg.  Patients will take the study drug sublingually daily at bedtime, starting on the 
day that they are randomized and continuing for 12 weeks (or to early termination).  A dynamic 
randomization procedure will be employed at Visit 2 to minimize trial-wide imbalances between 
the treatment groups for site, sex, current tobacco/nicotine use (yes/no) and presence (yes/no) of 
current Major Depressive Episode (MDE) based on the Mini International Neuropsychiatric 
Interview, Version 7.0.2 (M.I.N.I. 7.0.2) conducted at Visit 1. 
Patients who test positive for cocaine, ecstasy (MDMA), methamphetamine or other non-
disclosed illicit drugs (other than marijuana) should be screen-failed.  In addition, patients who 
meet M.I.N.I. criteria outlined in the entry criteria for alcohol/substance use disorder over the 6 
months prior to Screening should be screen-failed. 
Patients suffering from depression are eligible for the study, provided their depression does not 
pose an undue risk to their well-being (e.g., suicidal risk) or warrant treatment with 


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antidepressants or other excluded treatments.  The investigator will evaluate each patient’s 
medical and psychiatric history, current symptomatology, and the results of the MINI 7.0.2, BDI-
II, C-SSRS, and CAPS-5 from Visits 1 and 2, to determine whether it is appropriate for the 
patient to participate in the study.  In addition, each patient will undergo medical monitor pre-
randomization review to ensure agreement with the investigator’s assessment.   
NOTE:  Patients who use alcohol/marijuana but do not meet criteria for alcohol/substance use 
disorder (per Diagnostic and Statistical Manual of Mental Disorders [Version 5; DSM-5]) are 
otherwise suitable for the study provided that, in the judgment of the Investigator, this usage will 
not interfere with the patient’s ability to complete the study or provide reliable data.  Information 
related to marijuana and alcohol use will be collected at Screening. 
Patients with evidence of hepatic impairment secondary to hepatitis B or C at screening, or who 
are undergoing treatment for hepatitis, should be excluded.  Patients with stable and 
asymptomatic disease whose hepatic enzymes (aspartate aminotransferase [AST] or alanine 
aminotransferase [ALT]) satisfy the study’s entry criteria (< 3 times the upper limits of normal), 
may be allowed to proceed with randomization with prior Medical Monitor approval. 
CAPS-5, M.I.N.I. 7.0.2 and Columbia Suicide Severity Rating Scale (C-SSRS) interviews will 
be conducted by an approved and qualified individual(s) at each site who has successfully 
completed training on each instrument. 
If a patient scores a 2 or 3 on the suicidal ideation section of the C-SSRS at any visit (including 
the Screening visit), the investigator and patient should work together to implement a Safety 
Planning Intervention (SPI).  As described in detail in Section 11.3.3, 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. 
The study timeline and events schedule is provided in Appendix 1. 
7.2. 
Number of Patients and Treatment Assignment 
A total of approximately 550 patients will be randomized in a 1:1 ratio to treatment with TNX-
102 SL 5.6 mg (2 x 2.8 mg) tablets or identical SL placebo tablets.  See Section 13.2 for details 
regarding potential sample size adjustment. 
7.3. 
Study Endpoints 
7.3.1. 
Primary efficacy endpoint 
The primary efficacy endpoint will be the mean change from baseline in the total Clinician 
Administered PTSD Scale-Version 5 (CAPS-5) at Week 12. 


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7.3.2. 
Secondary efficacy endpoints 
7.3.2.1. 
Key Secondary Efficacy Endpoints 
The first two secondary efficacy endpoints listed below are considered key secondary endpoints 
and will be tested in that order: 
• CGI-I score (analyzed as a continuous variable) after 12 weeks of treatment. 
• Change from baseline in the SDS total score after 12 weeks of treatment. 
A fixed sequence procedure will be applied to the key secondary efficacy endpoints to adjust for 
multiplicity and to control for overall type I error. 
7.3.2.2. 
Other Secondary Efficacy Endpoints 
• Change from baseline in patients’ quality of sleep using the PROMIS Sleep 
Disturbance scale after 12 weeks of treatment. 
• Change from baseline in the disruption of work/school activities assessed using the 
SDS after 12 weeks of treatment. 
• Change from baseline in disruption of social life/ leisure activities assessed using the 
SDS after 12 weeks of treatment. 
• Change from Baseline in the disruption of family life/home responsibilities assessed 
using the SDS after 12 weeks of treatment. 
• Change from baseline in CAPS-5 Arousal and Reactivity (Criterion E) score after 12 
weeks of treatment. 
• Change from baseline in CAPS-5 Intrusion symptoms (Criterion B) score after 12 
weeks of treatment. 
• Change from baseline in CAPS-5 Persistent Avoidance (Criterion C) score after 12 
weeks of treatment. 
• Change from baseline in CAPS-5 Negative Cognition and Mood (Criterion D) score 
after 12 weeks of treatment. 
• Change from baseline in CAPS-5 Sleep Disturbance (item E-6) score after 12 weeks 
of treatment. 
• Change from baseline in CAPS-5 Exaggerated Startle (item E-4) score after 12 weeks 
of treatment.  
• PGIC score after 12 weeks of treatment. 
• Proportion of patients with a PGIC score of “much improved” or “very much 
improved” after 12 weeks of treatment 
• Proportion of patients with a treatment response on the CGI-I defined as a CGI-I 
score of “much improved” or “very much improved” after 12 weeks of treatment. 
• Proportion of patients with a Total CAPS-5 score of 0 –10 (asymptomatic/few 
symptoms) after 12 weeks of treatment. 


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• Proportion of patients with a Total CAPS-5 score of 0-22 (asymptomatic or mild 
PTSD/subthreshold) after 12 weeks of treatment. 
• Proportion of patients with Response, defined as a ≥ 10-point improvement from 
baseline in Total CAPS-5 score after 12 weeks of treatment. 
• Proportion of patients with Loss of Diagnosis, defined as Response AND no longer 
meeting DSM-5 symptom criteria in any one or more of the four clusters (B, C, D, E) 
after 12 weeks of treatment. 
• Proportion of patients in Remission, defined as Loss of Diagnosis AND Total CAPS-
5 score ≤ 10 after 12 weeks of treatment. 
• Proportion of patients achieving sustained Remission, defined as Loss of Diagnosis 
AND Total CAPS-5 score ≤ 10 after both 8 weeks AND 12 weeks of treatment.  
• Proportion of patients with a ≥50% improvement from baseline in Total CAPS-5 
score after 12 weeks of treatment. 
• Change from baseline in BDI-II score after 12 weeks of treatment. 
• Change from baseline in CAPS-5 Reckless or Self-Destructive Behavior (item E-2) 
score after 12 weeks of treatment.  
 
7.3.3. 
Exploratory efficacy endpoints 
Any exploratory endpoints will be delineated in the SAP. 
7.3.4. 
Safety 
Safety will be assessed by: 
• Adverse events (AE) and serious AEs (SAEs) throughout the entire duration of the 
study, including detailed assessment of AEs involving the oral cavity 
• Changes from baseline in clinical laboratory test results 
• Changes from baseline in vital signs and weight 
• Change from baseline in BDI-II 
• Changes from baseline indicative of increased suicidal ideation or behavior as 
assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) 
• Changes from baseline in patient-rated Changes in Sexual Functioning Questionnaire 
Short-Form (CSFQ-14) 
• Changes from baseline in patient-rated morning sedation as assessed by the Morning 
Treatment-Related Sedation Score (MTRSS) 


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7.3.5. 
Pharmacogenomic Endpoints 
In this present study, we propose to examine potential genetic determinants of treatment response 
and particular adverse events by studying the patient’s genomic profile in relation to treatment 
outcome and presence or absence of the adverse events. A single blood sample will be obtained 
at an unscheduled post-study visit, with invited participants first providing separate written, 
signed informed consent for pharmacogenomic analysis. The final list of pharmacogenomic 
endpoints will be delineated in the SAP for the pharmacogenomic portion of the study.  
7.4. 
Efforts to Minimize Missing Data 
It is important to avoid missing data from clinical trials.  The following strategies are designed to 
minimize drop-outs and missing data in this study: 
• Providing patients with greater background on the nature of placebo-controlled 
clinical trials and explaining that completing this study, regardless of the patient’s 
level of treatment response, is essential to understanding whether TNX-102 SL may 
be helpful to others in the treatment of PTSD.  Sites will explain that the study is not 
designed to benefit the individual patient but, rather, can only provide useful 
information for future therapeutics. 
• Minimizing the burden on patients, with visits scheduled generally every 4 weeks 
(with reasonable visit window flexibility).  Clinical site personnel will also receive 
guidance regarding the special considerations necessary when dealing with patients 
with military PTSD. 
• Training of site personnel on the importance of minimizing missing data 
• Providing payment for patients’ time and effort at clinic visits, based on the duration 
of assessments and as approved by the Institutional Review Board.  Reimbursement 
for travel expenses to and from the clinic sites may also be provided to further 
minimize the financial burden of participating in the study. 
• Utilizing repeated assessments of outcome measures and analytical approaches that 
most appropriately compensate for missing data. 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
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.  If 
medications are to be withdrawn for the explicit purpose of participation in this study, the patient 
must first sign an informed consent form before the withdrawal or down titration of any 
medication is initiated. 
Informed consent is documented by means of a written, signed, and dated informed consent form 
(ICF).  Separate written, signed informed consent must be obtained if the patient is to participate 


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in the post-study pharmacogenomic assessment. Additional information is provided in 
Section 15.3. 
8.2. 
Inclusion Criteria 
Patients enrolled in this study will be volunteer patients.  Eligible patients must meet all of the 
following inclusion criteria during the screening period: 
1. Male or female between 18 and 75 years of age, inclusive, with military service (defined 
as active duty military, National Guard, reservist, veteran or military contractor) 
Identification confirming military service will be checked prior to randomization; 
medical monitor approval will be required for potential patients unable to provide 
evidence of prior service.  
2. Diagnosed with current PTSD as determined by the Clinician-Administered PTSD Scale 
(CAPS-5) for Diagnostic and Statistical Manual of Mental Disorders-Version 5 (DSM-5) 
and of sufficient symptom severity, defined as all of the following at Screening Visit 1 
using the Diagnostic version (1-month recall): 
a. The A criterion is 1=YES, and 
b. At least ONE item of the B criterion items must have a score of ≥2, and 
c. At least ONE item of the C criterion items must have a score of ≥2, and 
d. At least TWO items of the D criterion items must have a score of ≥2, and 
e. At least TWO items of the E criterion items must have a score of ≥2, and  
f. The F item 22 criterion is 1=YES (≥1 month duration of symptoms) 
g. At least ONE item of the G items must have a score of ≥2, and 
h. The total CAPS-5 score (of items 1 through 20 is) ≥33. 
3. Index trauma(s) resulting in PTSD must meet the following: 
a. DSM-5 criterion A for PTSD as described in the CAPS-5 and Criterion A – 
Assessment Form (CA-AF), and 
b. Must have occurred in 2001 or later, and 
c. Must be military service related (either occurrence during military service, including 
during National Guard service or as reservist), and 
d. Must have occurred when the patient was ≥18 years of age.  
4. Willing and able to withdraw and refrain from opioids for the course of the study. 
5. Willing to refrain from use of all other formulations of cyclobenzaprine for the course of 
the study. 
6. Willing and able to refrain from antidepressants, antipsychotics, mood stabilizers, 
anticonvulsants, benzodiazepines, non-benzodiazepine hypnotics, buspirone, stimulants 
(e.g. amphetamines, methylphenidate, modafinil, armodafinil), prazosin and trazodone 
for the course of the study. 
7. Capable of reading and understanding English and able to provide written informed 
consent to participate.  
8. If female, either not of childbearing potential (defined as postmenopausal for at least one 
year or surgically sterile [e.g., bilateral tubal ligation; bilateral oophorectomy; 


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hysterectomy, etc.]) or practicing one of the following medically acceptable methods of 
birth control throughout the study: 
a. Hormonal methods such as oral, implantable, injectable, or transdermal 
contraceptives for a minimum of one full cycle (based on the patient’s usual 
menstrual cycle period) before study drug administration; 
b. Intrauterine device (IUD); 
c. Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with 
spermicidal jellies or cream); 
d. In sexually-exclusive relationship with vasectomized male partner, or in same-sex 
relationship with no plans for artificial or other forms of insemination. 
9. Willing and able to comply with all protocol-specified requirements. 
10. If patient has received trauma-focused treatment (e.g., cognitive behavioral therapy for 
PTSD, prolonged exposure therapy, desensitization therapy, etc.) must have been 
completed at least three months prior to the Baseline visit, and there can be no plans to 
initiate this type of therapy during study.  General psychotherapy that was in process at 
time of Screening may be continued during the trial, but no new initiation of treatment is 
allowed during the trial after enrollment. 
11. Separate written, signed informed consent will be required if the patient is to participate 
in the  post-study pharmacogenomic assessment. To be eligible to participate in the 
Pharmacogenomic assessment, the patient must have been randomized, had at least one 
post-baseline CAPS-5 assessment, and received active study drug in the TNX-CY-P301 
study.  
 
8.3. 
Exclusion Criteria 
Eligible patients who meet any of the following criteria during the screening period should be 
excluded from the study: 
1. Increased risk of suicide on the basis of the investigator’s judgment and/or the results of 
the Mini International Neuropsychiatric Interview, Version 7.0.2 (M.I.N.I. 7.0.2) 
conducted at Screening and the Columbia Suicide Severity Rating Scale (C-SSRS) 
conducted at Screening and/or Baseline. Any of the following will be exclusionary: 
a. High suicidality based on a M.I.N.I. Module B score ≥ 17 (Screening); or, 
b. Patient answers YES to either M.I.N.I. question B10 or B11 (Screening); or, 
c. Patient meets criteria for CURRENT Suicidal Behavior Disorder on the M.I.N.I 
(Screening); or, 
d. C-SSRS Type 4 or Type 5 ideation within 6 months of Screening or at the 
Baseline visit; or,  
e. Any suicidal behavior in the past 12 months as identified by the C-SSRS at 
Screening or Baseline. 
2. Increased risk of suicide, based on the investigator’s judgment that is of a severity that is 
not appropriate for outpatient management, or that warrants additional therapy excluded 
by the protocol. 


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3. Significant (e.g., moderate or severe) comorbid traumatic brain injury (TBI) by history.  
Based on past history and investigator’s judgment, patients with mild TBI are eligible. 
4. Evidence of severe depression at screening or baseline (Visits 1 or 2) based on the 
investigator’s judgment and collaborative pre-randomization review by the investigator 
and medical monitor(s) of the patient’s psychiatric history, presenting symptomatology, 
M.I.N.I. 7.0.2 (including Major Depressive Episode and Suicidality modules), C-SSRS, 
CAPS-5, and BDI-II assessments. 
5. Clinically significant laboratory abnormalities based on screening laboratory tests and/or 
medical history in the investigator’s opinion, including a Thyroid Stimulating Hormone 
(TSH) level >1.5 times the upper limit of normal and aspartate aminotransferase (AST) 
and/or alanine aminotransferase (ALT) > 3 times the upper limit of normal (if persistent 
upon repeat).  Patients with treated thyroid conditions and TSH levels < 1.5 times the 
upper limit of normal will be eligible to participate in the study. 
6. Diagnosed with clinically significant cardiac disease (e.g., significant arrhythmia or heart 
block, heart failure, or recent myocardial infarction [within the past 2 years]) or QTcF 
>450 msec (male) or >470 msec (female) on the screening electrocardiogram (ECG). 
7. Current evidence of human immunodeficiency virus (HIV) infection based on screening 
laboratory results or medical history, or clinically significant hepatitis B or C infection as 
defined by current treatment or liver function tests (e.g., aspartate aminotransferase 
[AST] or alanine aminotransferase [ALT] > 3 times the upper limits of normal). 
8. Use of antidepressant medication within 2 months of baseline, with the exception of 
trazodone used at doses ≤ 150 mg per day or tricyclic antidepressants at doses ≤25 mg 
per day, which instead require a 1-week drug-free interval prior to the Baseline visit. 
9. Unable to successfully wash out of the following medications during screening, or in 
whom washout is medically inadvisable: anticonvulsants, mood stabilizers, anti-psychotic 
agents, opioids, benzodiazepines, non-benzodiazepine hypnotics (zolpidem; eszopiclone, 
zaleplon), buspirone, trazodone, stimulants (e.g., amphetamine mixed salts, 
methylphenidate, lisdexamphetamine, dextroamphetamine, modafanil, armodafanil), 
atomoxetine,  or any medication known to be a potent (strong) cytochrome P450 subtype 
3A4 (CYP3A4) inhibitor, or St. John’s wort.  Note:  Use of caffeine and/or nicotine is 
permitted. 
10. Unable to successfully wash out of alpha-adrenergic antagonists and/or agonists (e.g., 
prazosin, terazosin, doxazosin, tamsulosin, silodosin, tizanidine, clonidine, guanfacine) or 
when washout is medically inadvisable. 
11. Positive results for illegal or abused substances other than cannabis at Screening or 
Baseline or history of alcohol/substance use disorder during the preceding 6 months as 
defined by the screening M.I.N.I. 7.0.2.  Patients who utilize alcohol/cannabis but do not 
meet criteria for alcohol/substance use disorder are otherwise suitable for the study 
provided that, in the judgment of the Investigator, this usage will not interfere with the 
patient’s ability to complete the study or provide reliable data. 
12. Any clinically significant, uncontrolled, or unstable medical or surgical condition that 
could affect a patient’s ability to participate in the study or potentially compromise a 


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patient’s well-being during the study, including patients with a history of untreated or 
uncontrolled angle-closure glaucoma.   
13. Diagnosis of DSM-5-defined bipolar disorder I, II or unspecified, schizophrenia, 
schizoaffective disorder, obsessive-compulsive disorder, major depressive disorder 
(MDD) with psychotic features, other psychotic disorder, or antisocial personality 
disorder as confirmed by the M.I.N.I. Version 7.0.2. 
14. History within the past 2 years of violent behavior unrelated to military duties or 
associated work. 
15. Anticipated need for surgery that might confound results or interfere with patient’s ability 
to comply with the protocol. 
16. Female patients who are pregnant or lactating. 
17. History of serotonin syndrome, severe allergic reaction or bronchospasm or known 
hypersensitivity to cyclobenzaprine or the excipients in TNX-102 SL or placebo 
formulations. 
18. Seizure disorder other than history of childhood febrile seizures. 
19. Current sleep apnea not well controlled by Continuous Positive Airway Pressure (CPAP) 
or oral (mouthpiece) devices.  Patients with mild obstructive sleep apnea or those well 
controlled by CPAP or oral (mouthpiece) devices are allowed at the discretion of the 
investigator. 
20. Patients with a body mass index (BMI) > 45. 
21. Has received any other investigational drug within 30 days before Screening or has taken 
cyclobenzaprine within 21 days before Randomization visit. 
22. Previous participation in any other study with TNX-102 SL. 
23. Any existing oral medical or dental condition, or tongue piercings, that could potentially 
interfere with sublingual administration of study drug, or history of severe or unexplained 
oral or oropharyngeal swelling or edema. 
24. Family member of investigative staff. 
25. In the process of litigating for compensation for a psychiatric disorder.  Patients who are 
in the process of applying for VA benefits or who have a settled claim are eligible. 
8.4. 
Randomization Criteria 
The following randomization criteria must be satisfied at the Visit 2 Baseline Randomization 
Visit in order for the patient to be eligible to continue in the study.  Only those patients meeting 
all of the following randomization criteria are eligible for randomization: 
1. Patient continues to meet all inclusion and exclusion criteria, including urine and 
blood test results, and 
2. Visit 2 total CAPS-5 score ≥ 33 (“Symptom Severity version using 1-week recall), 
and 


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3. At Visit 2, patient is not severely depressed (based on the investigator’s judgment and 
Visit 2 C-SSRS, CAPS-5, and BDI-II, and considering the pre-randomization 
collaborative review by the investigator and medical monitor(s) of the patient’s Visit 
1 psychiatric history, presenting symptomatology, M.I.N.I. 7.0.2, C-SSRS, CAPS-5, 
and BDI-II assessments).  
4. No active suicidal intent or plan, based on Investigator’s judgment, and Visit 2 C-
SSRS responses (e.g., no C-SSRS Type 4-5 ideation or suicidal behavior since Visit 
1). 
8.5. 
Prior and Concomitant Medications 
Many concomitant medications are prohibited during this study because this study has been 
designed to evaluate the safety and efficacy of monotherapy with TNX-102 SL tablets for the 
treatment of PTSD.  The goal of the study is to recruit patients who are not currently using other 
medications to treat their PTSD, or who are not clearly benefitting from any of the medications 
that would need to be discontinued in order to enter this study.  Since many patients with PTSD 
may already be taking one or more excluded medications when screened, Principal Investigators 
should use extreme caution when determining whether a patient, in their clinical judgment, can 
be safely withdrawn from current medications that are being used to treat PTSD or are otherwise 
excluded from the protocol. 
Eligible patients will not be receiving treatment with antidepressants, antipsychotic agents, mood 
stabilizers or anticonvulsants.  In addition, eligible patients will not have taken antidepressants 
within 2 months of the Baseline visit.  This time frame is intentionally long because it is not 
considered appropriate for patients to discontinue antidepressants solely to enter the study.  An 
exception is made for the use of low-dose tricyclic agents at doses ≤ 25 mg per day, or trazodone 
at doses ≤ 150 mg per day, either of which may be discontinued for the purpose of enrollment 
but requires a 1-week medication-free period prior to randomization, as described below. 
Patients also must be willing and able to discontinue use of benzodiazepines, non-
benzodiazepines and certain other medications frequently used to treat PTSD; e.g., prazosin; 
trazodone; topiramate.  Discontinuation of any of these agents should only be considered if/when 
the patient’s clinical condition and stability will not be adversely affected. 
Unless otherwise stated, excluded medications (e.g., trazodone, prazosin, topiramate, alpha- 
adrenergic agonists or antagonists [e.g., prazosin; tamsulosin; terazosin; doxazosin, silodosin, 
alfuzosin, clonidine, guanfacine], buspirone, benzodiazepines, and non-benzodiazepine 
hypnotics [zolpidem, zaleplon, eszopiclone]) will require a 1-week drug-free period prior to the 
Baseline visit (Visit 2).  Similarly, all opioid medications, including tramadol and tapentadol, are 
excluded medications.  Patients on chronic opioids are not appropriate candidates for 
participation, but there may be patients with occasional PRN opioid usage or who were recently 
on a short course for acute pain who may be appropriate if, in the clinical judgement of the 
Investigator, they could be safely tapered and remain opioid free for the week before baseline 
visit and throughout the 12 weeks of the study.  The screening period of up to 35 days is 
provided to ensure a safe tapering rate and discontinuation of excluded medications, per 
Investigator’s discretion, leading up to the 1-week medication-free period required before the 
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Other medications capable of modifying the pharmacologic activity of TNX-102 SL (e.g., α-
adrenergic agonists/antagonists; potent CYP3A4 inhibitors) will also be excluded, and 
discontinuing these medications should only be considered if clinically acceptable.  A list of 
CYP3A4 inhibitors is provided in 0; only those considered potent or strong inhibitors (in the left-
hand column) are excluded medications.   
8.5.1. 
Allowed Concomitant Medications 
It is ideal to have all patients participating in the study go without any hypnotic agents for the 
entire double-blind period of the study.  Yet there may be instances in which patients’ insomnia 
symptoms need to be addressed with a concomitant treatment.  In these instances, the 
Investigator should recommend use of an antihistamine-based OTC hypnotic, such as Benadryl® 
or generic diphenhydramine 25-50 mg, for a limited period (e.g. no more than a few nights in a 
row).  Patients should be asked to keep track of their use of such sleeping remedies, and again, 
chronic nightly use should be avoided whenever possible.   
Melatonin is considered an allowable concomitant medication but its usage should have been 
stable for at least 30 days prior to baseline and usage should remain stable during the study.  If 
diphenhydramine is ineffective, the treating Investigator should contact the medical monitor to 
discuss alternative options.    
Allergy medications and cold remedies containing adrenergic agonist decongestants such as 
pseudoephedrine or phenylephrine should be avoided unless absolutely necessary (and in such 
cases when considered absolutely necessary, they should be avoided in the evening or at bedtime 
to minimize their interference with sleep).  Sympathomimetics such as adrenergic agonist 
decongestants have the potential to acutely worsen PTSD symptoms and therefore could 
confound the assessment of TNX-102 SL versus placebo for treatment of PTSD. 
Other prescription or over-the-counter medications not specifically excluded by entry criteria 
typically may be continued during the study, with the expectation that chronic medications 
should have been used in a stable fashion for at least 30 days prior to randomization.  Sites 
should contact the medical monitor for any questions about whether a concomitant medication 
may be continued during the study or if it would be acceptable to taper an excluded medication. 
8.6. 
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 10.5.1. 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drug Packaging, and Labeling and Storage 
Study drug supplies will be packaged identically so as to maintain the integrity of the study 
blind.  The study medication bottles will be labeled minimally with the following information:  
study number TNX-CY-P301, sponsor name and address, bottle number, quantity, storage 


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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.  Two bottles will be dispensed to each 
patient at Visit 2 (baseline), Visit 4 (Week 4) and Visit 5 (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) as defined 
in the Study Reference Manual (IP Receipt and Storage) are permitted without the sponsor’s 
approval. 
9.2. 
Dosing Instructions 
Patients will be instructed to take two tablets of their assigned study drug (TNX-102 SL 2.8 mg 
tablets or placebo tablets) sublingually, placed simultaneously under the tongue, each evening 
at bedtime starting at bedtime on evening of Day 0 (Day of Visit 2) 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 SL 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 2 (two) 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. 
9.3. 
Dispensing Instructions 
Each patient who has met the randomization criteria (Section 8.3) will be assigned 2 double-
blind treatment bottles at Visit 2 via the IWRS, with a unique, but otherwise random bottle 
number that is generated when the study coordinator successfully completes randomization 
procedures.  Patients will also be assigned two new treatment bottles at Visits 4 and 5 via the 
IWRS.  The bottle numbers provided by the Interactive Web Response (IWR) system at these 
visits will tell the site which treatment bottles have been assigned to the patient. 
In the event of loss of study medication, new medication will be provided by the IWR system, 
when appropriately requested by the site and/or the sponsor or designee. 
Study treatments for the double-blind treatment phase are either: 


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Treatment A: 2 × TNX-102 SL 2.8 mg tablets (“TNX-102 SL”) to be taken sublingually 
once daily at bedtime. 
Treatment B: 2 × placebo tablets (“placebo”) to be taken sublingually once daily at bedtime. 
9.4. 
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. 
9.5. 
Study Drug Accountability and Reconciliation 
All patients will be expected to bring their bottles of study medication with them to all study 
visits.  At each study visit, the site staff will inspect the medication bottles, and 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.  Patients will be asked for an 
explanation if the count of returned study drug tablets indicates a discrepancy between the 
expected number of tablets dosed and the number returned in the bottles.  If it is found that the 
patient is not taking the study medication as expected, the patient will be re-counseled with 
instructions, and this should be noted in the patients’ records.  A deviation should be recorded on 
any patient who is less than 70% compliant with dosing between visits. 
If the patient fails to return any of the unused study drug as expected, the patient should be 
questioned regarding the reason for the lower than expected tablet number and about potential 
misuse, abuse or diversion.  If more than 8 tablets cannot be accounted for at any of the visits 
where drug is returned (week 4, 8 or 12), the investigator will be asked to evaluate the situation, 
and a written summary of this evaluation should be added to the source and entered onto the case 
report form (CRF).  Situations where replacement drug is requested, or when more than 8 tablets 
cannot be accounted for, should be recorded as deviations.   
All study medication, including partial and empty bottles, must be maintained at the study site 
until Tonix or its designee verifies drug accountability and provides instruction for 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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10. 
STUDY VISITS AND PROCEDURES 
The overall and detailed schedule for study procedures and visits is provided in Appendix 1. 
10.1. 
Visit 1 (Screening: Day -35 to -7) 
10.1.1. 
Informed Consent 
Before the potential patient has undergone any study-related screening procedures, including any 
downward titration or withdrawal of medications, 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. Separate written, signed informed consent must be obtained if the 
patient is to participate in the post-study pharmacogenomic assessment. 
10.1.2. 
Screening Overview 
Screening Visit 1 will start a variable length screening period.  The length of the screening 
period is to be no shorter than 7 days, but may be as long as 35 days in order to accommodate 
medication taper and discontinuation or other study requirements. 
If the patient is eligible to continue in the study, and does not need to discontinue any excluded 
medication, the patient may be scheduled to return for Visit 2 (Randomization) in 7 (or more) 
days, assuming all screening evaluations have been completed, including confirmation of 
acceptable laboratory and ECG results.  If the patient needs to undergo taper and discontinuation 
of excluded medication, the Investigator will generate a written down titration schedule for the 
patient and will schedule Visit 2 such that the date of Visit 2 is at least 1 week after the date of 
the final dose of any excluded medication.  If additional clinic visits are deemed necessary by the 
investigator for clinical monitoring of the patient before scheduling Visit 2, such visits will be 
recorded as unscheduled visits. 
10.1.3. 
Patient Numbering 
All screened patients will be assigned a unique concatenated 6-digit site-patient number (e.g., 
102-112) by the IWR system.  A screening log or system documenting the following information 
will be recorded and maintained, and will include the patient’s initials, screening number, 
whether the patient was ultimately randomized or not, and if not randomized, the reason the 
patient was excluded/screen-failed. 
10.1.4. 
Screening and Assessments/Procedures 
The following screening assessments/procedures will be completed in the following general 
order: 
• Obtain written informed consent to participate 


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• Obtain demographics, including alcohol, nicotine/tobacco (smoking and/or chewing), and 
marijuana use 
• Obtain medical history  
• Obtain prior and current medication history, including all prior PTSD therapies and other 
treatments for psychiatric indications  
• Obtain psychiatric history (M.I.N.I. 7.0.2) 
• Administer PTSD Rating Scales: 
o Life Events Checklist (LEC-5) 
o Criterion A – Assessment Form (CA-AF) 
o Clinician Administered PTSD Scale (CAPS-5) (Since Last Month version)  
• Perform physical examination, including visual inspection of the oral cavity (including 
floor of mouth/sublingual area)  
• Obtain vital signs, height, weight and BMI 
• Draw samples for clinical laboratory tests for: 
o Chemistry, hematology, HIV and TSH, with free thyroxine also performed if TSH 
is outside the upper or lower limits of normal 
o Urine Drug Screen (central laboratory) 
o Serum pregnancy test (for women of child-bearing potential) 
• Conduct 12-lead electrocardiogram  
• Administer Depression/Suicidality Scales 
o Beck Depression Inventory (BDI-II) 
o Columbia Suicide Severity Rating Scale (C-SSRS, Baseline/Screening Version, 
with rater review of BDI-II prior to starting C-SSRS interview)  
• Review inclusion/exclusion criteria 
Only those patients meeting all of the inclusion and none of the exclusion criteria will be eligible 
to continue.  NOTE:  Final determination of eligibility based on clinical laboratory tests will be 
made when results have been returned. 
Sites will be asked to complete and submit to the Tonix medical monitoring team key screening 
information.  This information will be reviewed by the Tonix medical monitoring team to help 
ensure the selection of well-qualified patients.  The specific requirements and timelines 
associated with this pre-randomization review process will be outlined in a separate document. 
Once eligibility has been confirmed and authorization for randomization granted by a Tonix 
medical monitor, eligible patients will return to the clinic for Visit 2. 
There is no requirement for Follow-Up visits for patients who are screen failures.  Patients who 
fail to qualify should have their medication adjusted, as appropriate, per the judgment of the 


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Investigator and be released from the clinic.  There will be no requirement to enter data into the 
electronic case report form (eCRF) for patients who are not randomized. 
10.2. 
Visit 2 (Baseline: Day 0) 
Visit 2 should be scheduled 7 to 35 days after Visit 1.  Study procedures will be completed 
(including qualifying baseline assessments for the C-SSRS and CAPS-5).  If the patient meets all 
randomization criteria, the patient will be randomized via the IWR system to receive double-
blind study medication. 
10.2.1. 
Pre-Randomization Assessments 
The following assessments must be completed at Visit 2 to confirm that the patient is eligible for 
randomization.  Upon arrival at the clinic, the following assessments should be done, preferably 
in this order: 
• Assess occurrence of adverse events 
• Update medical history (with changes since screening noted) 
• Assess changes in medication history and concomitant medications 
• Obtain vital signs and weight 
• Administer CAPS-5 - “Symptom Severity Version”, using 1-week recall 
• Conduct urine drug screen (urine dipstick, only as necessary, if select Visit 1 tests were 
positive for excluded medications that required discontinuation prior to randomization) 
• Conduct urine pregnancy test (for women of child-bearing potential)  
• Perform visual examination of the oral cavity  
• Have the patient complete the following outcome scales (in order): 
o SDS 
o PROMIS scale for sleep disturbance 
o MTRSS (assessment of sedation) 
o CSFQ-14 
o BDI-II (needs to be completed prior to the C-SSRS and reviewed by the C-SSRS 
rater at outset of C-SSRS interview) 
• Administer the C-SSRS- Since Last Visit Version (with rater review of BDI-II prior to 
starting C-SSRS interview) 
10.2.2. 
Randomization Criteria 
Once all pre-randomization assessments have been completed, only those patients who meet all 
of the following randomization criteria will be eligible to continue: 
1. Patient continues to meet all inclusion and exclusion criteria, including urine and blood 
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2. Visit 2 total CAPS-5 score ≥ 33 (“Symptom Severity” version using 1-week recall), and 
3. At Visit 2, patient is not severely depressed (based on the investigator’s judgment and 
Visit 2 C-SSRS, CAPS-5, and BDI-II, and considering the pre-randomization 
collaborative review by the investigator and medical monitor(s) of the patient’s Visit 1 
psychiatric history, presenting symptomatology, M.I.N.I. 7.0.2, C-SSRS, CAPS-5, and 
BDI-II assessments).  
4. No active suicidal intent or plan, based on Investigator’s judgment, and Visit 2 C-SSRS 
responses (e.g., no C-SSRS Type 4-5 ideation or suicidal behavior since Visit 1). 
If the patient does not satisfy these randomization criteria, the patient has failed to qualify for 
this study and should be considered a screen failure, with the reason documented.  With Medical 
Monitor approval, if the patient is otherwise considered a qualified and compliant patient, Visit 2 
may be delayed to accommodate situations in which extenuating or short-term circumstances do 
not warrant screen failure. 
If the patient does satisfy these randomization criteria, then continue with the following: 
• Randomize the patient via IWRS Randomization System 
• Dispense 4-week supply (two bottles) of double-blind study medication 
• Review patient instructions regarding study drug dosing (Section 9.2) 
• Schedule next study visit 
10.3. 
Visit 3 (Telephone Visit: Day 14) 
Visit 3 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.  
• Administer the ‘Since Last Visit’ C-SSRS 
After all of the items have been reviewed with the patient, the patient should be given an 
appointment to return to the clinic for Visit 4, and be re-instructed, as necessary, on dosing 
instructions, and reminded to bring study medication back to the clinic at their next visit. 
10.4. 
Visit 4 and 5 (Weeks 4 through 8) 
Visits 4 and 5 are similar study visits that are scheduled to be conducted after 4 and 8 weeks of 
treatment, respectively.  Visit 4 should occur on Day 28 ± 5 days and Visit 5 should occur on 
Day 56 ± 5 days. 


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The following assessments and procedures are scheduled for these visits in the following general 
order: 
• Collect study drug and assess compliance 
• Assess occurrence of adverse events 
• Update concomitant medications 
• Obtain vital signs and weight 
• Administer CAPS-5-“Symptom Severity Version” using 1-week recall 
• Conduct urine pregnancy test (for women of child-bearing potential) 
• Have the patient complete the following outcome scales (in order): 
o SDS 
o PROMIS scale for sleep disturbance 
o MTRSS (assessment of sedation) 
o PGIC 
o BDI-II (needs to be completed prior to the C-SSRS and reviewed by the C-SSRS 
rater at outset of C-SSRS interview) 
• Administer C-SSRS - Since Last Visit Version 
• Physician to assess CGI-I (needs to be completed once all other assessments are available 
for investigator to review) 
• Dispense new bottles of double-blind study medication as assigned by IWRS 
After all of the assessments at each visit have been completed, the patient should be given an 
appointment to return to the clinic for the next scheduled visit, and be re-instructed, as necessary, 
on dosing instructions, and reminded to bring study medication back to the clinic at their next 
visit. 
10.5. 
Visit 6 (Week 12) 
Visit 6 should occur after 12 weeks of double-blind study drug treatment, scheduled at Day 84 -5 
/ +7 days.  The following assessments and procedures are to be completed in the following 
general order: 
• 
Collect study drug and assess compliance 
• 
Assess occurrence of adverse events 
• 
Update concomitant medications  
• 
Obtain vital signs and weight 
• 
Administer CAPS-5-“Symptom Severity Version” using 1-week recall 
• 
Conduct urine pregnancy test (for women of child-baring potential). Serum pregnancy 
test may be done at Investigator’s discretion.  


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• 
Draw samples for clinical laboratory tests for: 
− Chemistry and hematology 
• 
Perform visual examination of oral cavity  
• 
Have the patient complete the following outcome scales (in order): 
o SDS 
o PROMIS scale for sleep disturbance 
o MTRSS (assessment of sedation) 
o PGIC 
o CSFQ-14 
o BDI-II (needs to be completed prior to the C-SSRS and reviewed by the C-SSRS 
rater at outset of C-SSRS interview) 
• 
Administer C-SSRS-Since Last Visit Version 
• 
Physician to assess CGI-I (needs to be completed once all other assessments are available 
for investigator to review) 
10.5.1. 
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 
This study will attempt to obtain as complete information as possible on all participating 
patients.  An effort must be made to contact the medical monitor prior to any patient’s early 
termination.  Each reason for early termination will be adjudicated.  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 study medication.  NOTE:  These visit procedures are not intended for patients who fail 
to qualify for randomization or for any other reason withdraw from the study prior to receipt of a 
dose of double-blind study drug. 


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If the patient withdraws prior to the week 2 (visit 3) visit window (before day 11), the following 
assessments and procedures are to be completed at this visit in the following general order: 
• 
Document reason for early termination 
• 
Collect study drug and assess compliance 
• 
Assess occurrence of adverse events 
• 
Update concomitant medications 
• 
Obtain vital signs and weight 
• 
Conduct urine pregnancy test (for women of child-bearing potential). Serum pregnancy 
test may be done at Investigator’s discretion. 
• 
Draw samples for clinical laboratory tests for: 
o Chemistry and hematology 
• 
Perform visual examination of oral cavity 
• 
Have the patient complete the following outcome scales (in order): 
o MTRSS (assessment of sedation) 
o CSFQ-14 
o BDI-II (needs to be completed prior to the C-SSRS and reviewed by the C-SSRS 
rater at outset of C-SSRS interview) 
• 
Administer C-SSRS – Since Last Visit Version 
If the patient withdraws after the week 2 (visit 3) visit window (on or after day 11), the following 
assessments and procedures are to be completed at this visit in the following general order: 
• 
Document reason for early termination 
• 
Collect study drug and assess compliance 
• 
Assess occurrence of adverse events 
• 
Update concomitant medications 
• 
Obtain vital signs and weight 
• 
Administer the CAPS-5-“Symptom Severity Version” using 1-week recall 
• 
Draw samples for clinical laboratory tests for: 
o Chemistry and hematology 
o Serum pregnancy test (for women of child-bearing potential) 
• 
Conduct visual examination of oral cavity 
• 
Have the patient complete the following outcome scales (in order): 
o SDS 
o PROMIS scale for sleep disturbance 


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o MTRSS (assessment of sedation) 
o PGIC 
o CSFQ-14 
o BDI-II (needs to be completed prior to the C-SSRS and reviewed by the C-SSRS 
rater at outset of C-SSRS interview) 
• 
Administer C-SSRS- Since Last Visit Version 
• 
Physician to assess CGI-I (needs to be completed once all other assessments are 
available for investigator to review) 
 
Once these assessments have been completed, the patient may be discharged from the study, 
provided that there is no need for additional follow-up to continue to monitor an adverse event or 
other condition.  
10.5.2. 
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 results, physical 
examination, or other findings.  If an additional study visit is warranted, or occurs, the date and 
nature of the visit will be documented in the CRF and in the source documents. 
Patients who call to report an oral AE that is a lesion of some form should be brought back to the 
clinic for an unscheduled oral exam if deemed appropriate. In the case in which the AE is solely 
sensory in nature (such as oral hypoaesthesia) and the patient reports there is no discernable 
associated lesion, an unscheduled oral exam is not required but may be arranged if the 
investigator determines it to be clinically appropriate. 
 
10.6. 
Pharmacogenomic Assessment (Post-Study) 
For patients who participated in P301 and are invited back to the site for participation in the 
optional pharmacogenomics assessment after having finished their participation, the patients will 
be invited in for an unscheduled visit in which they first will learn about the pharmacogenomics 
study and sign a separate written pharmacogenomics informed consent form. Next, a blood 
sample is drawn and processed for pharmacogenomic analysis. Once completed, the patient is 
discharged from the pharmacogenomics portion of the study. 


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11. 
STUDY ASSESSMENTS 
11.1. 
Screening Assessments 
11.1.1. 
Psychiatric and Medical History 
A psychiatric interview using the Mini International Neuropsychiatric Interview (M.I.N.I.-
Version 7.0.2) and a comprehensive medical history will be obtained at screening in order to 
determine whether the patient is eligible for enrollment. 
While patients with mild traumatic brain injury (TBI) are eligible to participate in the study, 
moderate and severe TBI are excluded.  Mild TBI (or concussion) is one of the most common 
forms of combat-related injury.  Based on self-report data, approximately 15% of troops engaged 
in active combat in Afghanistan and Iraq may have suffered a mild TBI (Hoge et al., 2008).  A 
history of TBI is defined as any traumatically induced structural injury and/or physiological 
disruption of brain function as a result of an external force that is indicated by new onset or 
worsening of at least one of the following clinical signs, immediately following the event: 
1. Any period of loss of or a decreased level of consciousness; 
2. Any loss of memory for events immediately before or after the injury; 
3. Any alteration in mental state at the time of the injury (e.g., confusion, disorientation, 
slowed thinking); 
4. Neurological deficits (e.g., weakness, balance disturbance, praxis, paresis/plegia, change 
in vision, other sensory alterations, aphasia) that may or may not be transient;  
5. Intracranial lesion. 
Although severity of TBI depends in part on patient assessment in the days after a traumatic head 
injury, for the purposes of this protocol, mild TBI is defined as: 
1. Normal structural brain imaging findings 
2. Loss of consciousness not greater than 30 minutes after injury 
3. Alteration of consciousness not greater than 24 hours after injury 
4. Posttraumatic amnesia not more than 24 hours after injury 
5. No ongoing neurological deficits (Note: tinnitus, headaches, or sleep disturbances that 
appeared to result from the head trauma would not be considered as ongoing neurological 
deficits and therefore should not be interpreted as meaning the person has a greater 
severity than mild TBI.) 
In addition, the past medication history will be reviewed.  Any psychiatric medication or PTSD 
therapies utilized during the patient’s lifetime should be collected.  Responses from the M.I.N.I. 
will serve to document the presence of other psychiatric conditions.  The diagnosis and severity 
of PTSD will be based on the CAPS-5 (Section 11.2.1). 
11.2. 
Efficacy Assessments 
The primary efficacy endpoint and many of the secondary and exploratory efficacy endpoints in 
this study are derived from clinician-administered assessments which must be administered by 
qualified and trained individuals at each clinical site.  Study specific training will be required 
before staff is allowed to administer these scales.  In an attempt to minimize variability in 


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responses of a given patient over time, it is important that the same rater administer the scales to 
a given patient throughout the study unless absolutely unavoidable due to the rater’s absence 
from the clinic.  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, appropriate privacy and sufficient time to 
complete them. 
11.2.1. 
Clinician-Administered PTSD Scale (CAPS-5) 
The primary efficacy endpoint is the change from baseline (Visit 2) in total CAPS-5 score at 
Week 12 (Visit 6). 
The CAPS-5 is an updated and validated version of a semi-structured interview that has been 
designed to assess the essential features of PTSD as defined by the DSM-5 (Weathers et al, 
2013).  The CAPS-5 affords the clinician flexibility to inquire about symptoms and diagnostic 
status over different time frames, such as past week, past month, and/or worst month for lifetime.  
For this study, a “Diagnostic” version of the CAPS-5 (lifetime and past month recall) will be 
utilized at the Screening visit to confirm the diagnosis of PTSD and determine eligibility based 
on symptom severity.  A “Symptom Severity” version of the CAPS-5 (past week recall) will be 
completed by clinician at all other time points (Baseline [Visit 2] and after 4, 8, and 12 weeks of 
treatment [Visits 4, 5, and 6]).  A CAPS-5 total score of 33 or above at both Screening 
(“Diagnostic” version) and Baseline (“Symptom Severity” version) is requisite for eligibility. 
In addition to the total symptom score, the CAPS-5 affords the opportunity to examine clusters 
of symptoms, including Criterion B (intrusion symptoms), Criterion C (persistent avoidance), 
Criterion D (negative cognitions and mood), and Criterion E (arousal and reactivity), all of which 
will be secondary efficacy endpoints. 
The CAPS-5 interview contains the following components: 
• 
Life Events Checklist for DSM-5 (LEC-5):  Completed by the patient at Screening Visit 1 
only) and reviewed by the rater of the CAPS-5 interview at the start of the interview. 
• 
PTSD Symptoms 
o Criterion A: the rater will review the patient-completed LEC-5 and then inquire into 
the qualifying index trauma (Criterion A) utilizing the study-specific Criterion A - 
Assessment Form (CA-AF) (Visit 1 only) 
o Criterion B: Items 1-5 
o Criterion C: Items 6-7 
o Criterion D: Items 8-14 
o Criterion E:  Items 15-20 
o Criterion F: Items 21-22 
o Criterion G: Items 23-25 
o Global ratings: Items 26-28 
o Dissociative symptoms: Items 29-30 


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Further instruction on when to complete each component will be provided in the study specific 
versions of the CAPS-5 forms. 
The LEC-5, which documents the patient’s lifetime traumatic experiences, will be completed by 
the patient at Screening Visit 1 before the clinician administered CAPS-5.  The CAPS-5 rater 
will be responsible for reviewing the answers on this form with the patient as part of the 
completion of the CAPS-5 Criterion A - Assessment Form in order to determine if the traumatic 
experience qualifies the patient for inclusion in the study.  NOTE:  If worst month lifetime PTSD 
symptoms resulted from earlier trauma(s), such as trauma(s) before age 18 or trauma(s) not 
related to military services, the prospective patient should be excluded from participation. 
At Screening, the total CAPS-5 score (Diagnostic version with 1-month recall) must be ≥ 33 and 
must meet the other diagnostic criteria specified in Inclusion Criterion 2 (Section 8.2) in order 
for the patient to continue.  At Baseline (Visit 2), the total CAPS-5 score (past week recall) must 
again be ≥ 33. 
The CAPS-5 interview must be completed by a qualified and trained rater.  This rater should be 
kept consistent for a given patient throughout the study.  If circumstances require non-conformity 
with the single rater approach for any patient, this should be documented.  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. 
11.2.2. 
Beck Depression Inventory (BDI-II) 
The Beck Depression Inventory (BDI-II) is a 21-item measure of the severity of current 
depressive symptoms, extensively validated for use in both medical and mental health 
populations.  While this instrument does not provide a psychiatric diagnosis of depression and 
has considerable overlap with PTSD associated symptoms (Resick et al, 2017), it does provide a 
continuous scale for measuring changes in the severity of symptomatology.   
The patient will be asked to complete this questionnaire at all in-clinic study visits.  At Visit 1 
and Visit 2, patients whose responses are indicative of suicidal ideation, as defined by a response 
to Item #9 of ≥1 should be carefully evaluated and compared to the patient’s C-SSRS responses, 
and appropriate intervention prescribed, if indicated.  In addition, patients’ BDI-II responses at 
Screening and Baseline (Visits 1 and 2) should be reviewed by the investigator as part of the 
comprehensive evaluation of the patient’s psychiatric status and overall eligibility, since patients 
suffering from severe depression should be screen failed and referred for appropriate 
psychological evaluation or care, as necessary.  After Visit 1, the responses to Item #9 should be 
monitored along with C-SSRS responses to ensure that there is no increase in suicidal ideation 
during the study, and the total score should also be monitored to ensure the patient’s 
psychological status remains stable. 
11.2.3. 
Clinical Global Impression of Improvement (CGI-I) 
The CGI-I will be completed by an Investigator to evaluate the patient’s status since initiation of 
treatment.  The CGI-I, status since initiation of treatment, is the first key secondary efficacy 
endpoint in this study.  The CGI-I should be completed toward the end of each in-clinic post-
Baseline study visit once all of the assessments are available for the investigator’s review.   


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11.2.3.1. CGI-I Assessments at Weeks 4, 8, and 12 
Once the patient has been randomized, an Investigator will complete the CGI-I assessment after 
4, 8, and 12 weeks of treatment (Visits 4 -6) in order to assess the overall change in the patient’s 
status since Baseline and answer the following question: 
Since the initiation of treatment at Visit 2, the patient is: 
1 = Very much improved 
2 = Much improved 
3 = Minimally improved 
4 = No change 
5 = Minimally worse 
6 = Much worse 
7 = Very much worse 
11.2.4. 
Patient Global Impression of Change (PGIC) 
The PGIC is a validated, self-report instrument to gauge the patient’s assessment of change in 
condition.  This form will be completed by the patient after 4, 8 and 12 weeks of treatment 
(Visits 4, 5 and 6, respectively).  The patient will answer a single question: 
Since the initiation of study medication, overall, my PTSD symptoms are: 
1 = Very much improved 
2 = Much improved 
3 = Minimally improved 
4 = No change 
5 = Minimally worse 
6 = Much worse 
7 = Very much worse 
11.2.5. 
PROMIS Sleep (short form) 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 Sleep scale (short form 8a) will be assessed at Baseline (Visit 2) and after 4, 8, and 
12 weeks of treatment (Visits 4, 5, and 6, respectively). 
11.2.6. 
Sheehan Disability Scale (SDS) 
The SDS scale is a self-report questionnaire that was designed to assess the patient’s view of the 
degree to which symptoms have disrupted work, social life/ leisure activities, and family life/ 
home responsibilities during the past 1 week (Sheehan & Sheehan, 2008).  In addition, the SDS 
asks the patient to provide the number of days or work lost as well as unproductive days in the 
past week.  The SDS scale will be completed by the patient at Baseline (Visit 2), and after 4, 8, 
and 12 weeks of treatment (Visits 4, 5, and 6, respectively).  


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11.3. 
Safety Parameters 
Safety will be assessed by evaluation of adverse events, responses on the C-SSRS and BDI-II, 
clinical laboratory tests, vital signs, weight, patient ratings of sexual function assessed by the 
CSFQ-14, and patient-rated assessments of morning sedation as assessed by the MTRSS. 
11.3.1. 
Adverse Events (AEs) 
Patients will be monitored for AEs throughout the study from the time that the patient signs an 
informed consent and 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, in the opinion of the 
patient and outside of their normal experience, should be reported as an adverse event. 
If a patient reports an oral cavity adverse event, the Investigator should examine the oral cavity 
to confirm the presence or absence of any irritation or other signs.  Additional details related to 
onset, duration, severity and reversibility of the oral cavity event will be documented 
(Section 11.3.5). 
Additional information regarding definition and reporting requirements for adverse events, 
serious adverse events, and pregnancies is provided in Section 11.3.1. 
11.3.2. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire 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 used 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. 
There are multiple versions of this questionnaire.  At Visit 1, the “baseline/screening” 
questionnaire will be administered and the recall periods will be “lifetime” and “within the past 6 
months” for suicidal ideation, and “within the past year” for suicidal behaviors.  Patients whose 
responses are indicative of suicidal ideation with intent and/or plan (e.g., Type 4-5 ideation) 
within the past 6 months or a history of prior suicidal behavior within the past year will be 
excluded from participation, with recommended referral for appropriate intervention. 


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At all subsequent visits (Visit 2 through 6), the “since last visit” questionnaire will be 
administered, and the recall period on this will be “since the last visit”.  Note that if there has 
been a significant change in responses indicative of increased suicide risk, appropriate 
intervention should be prescribed as described below. 
11.3.3. 
Safety Planning Intervention (SPI) 
The C-SSRS is completed at every visit in order to assess for changes in suicidality during the 
study.  As a screening and baseline entrance criterion, patients exhibiting Type 4 or 5 ideation in 
the past 6 months or a history of suicidal behavior in the past 12 months are not eligible for the 
study due to this risk and should be referred for appropriate emergency care.  If a patient scores a 
4 or 5 at a clinic visit following randomization, the patient should be withdrawn from the study 
and referred for appropriate emergency care.  If a patient scores a 4 or 5 at any clinic visit, it 
should be reported as a serious adverse event. 
If a patient scores a 2 or 3 on the suicidal ideation section of the C-SSRS at any visit (including 
the Screening visit), the investigator and patient should work together to implement a Safety 
Planning Intervention (SPI).  In addition, if a post-baseline score of 2 or 3 represents a significant 
change from the patient’s baseline status, it should be recorded as an adverse event. 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.  Additional information and training on the implementation of an 
SPI will be provided prior to initiation of the study. 
11.3.4. 
Physical Examination 
A complete physical examination will be performed at Screening Visit 1 only.  At a minimum, 
the physical examination will include the following components: HEENT (head, eyes, ears, nose, 
and throat), neck, chest and lungs, cardiovascular, abdomen, skin, and musculoskeletal.  The 
physical examination may exclude rectal, genitourinary, and breast examinations. 
11.3.5. 
Visual Examination of Oral Cavity 
A visual examination of the oral cavity should be done at Screening (Visit 1), Baseline (Visit 2) 
and after 12 weeks (Visit 6) 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 spontaneously reports an oral adverse event (other than 
transient sensory AEs such as tongue numbness, tingling or bitter taste) to confirm presence or 
absence of any irritation or other signs.  Additional details related to onset, duration, severity and 
reversibility of oral events will be documented in the CRF. 
11.3.6. 
Vital Signs, Height and Weight 
Vital signs (sitting blood pressure and heart rate, respiratory rate, oral temperature, and weight) 
will be assessed at Screening (Visit 1), Baseline (Visit 2) and after 4, 8, and 12 weeks of 
treatment (Visits 4, 5, and 6/Early Termination).  Height will be measured without shoes at Visit 


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1 only.  The BMI will be a derived variable, based on height and weight entries.  A BMI > 45 is 
an exclusion criterion. 
11.3.7. 
Electrocardiogram (ECG) 
A 12-lead ECG will be performed at Screening (Visit 1) and will be reviewed by the Investigator 
for the purpose of excluding from participation patients who have either a history of or current 
evidence of clinically significant cardiac disease (e.g., significant arrhythmias or heart block, 
heart failure, or myocardial infarction within the past 2 years) or a QTcF at Screening >450m/sec 
(males) or QTcF >470m/sec (females). 
The ECG interpretation by the Investigator will be recorded in the CRF as normal, abnormal but 
clinically insignificant, or abnormal and clinically significant.  In addition, the standard ECG 
parameters including rhythm, heart rate, and intervals for PR (or PQ), QRS, and QTcF 
(Fridericia’s) corrections for heart rate will be recorded. 
If the Investigator has any concerns about the eligibility of a patient or wishes to confirm his/her 
assessment, the Investigator should consult with the medical monitor for this study. 
11.3.8. 
Clinical Laboratory Assessments 
The clinical laboratory evaluations to be performed in this trial are listed in Table 2.  Those 
marked as screening tests will be performed at screening only.  All other tests will be performed 
at Screening (Visit 1) and after 12 weeks of treatment (Visit 6), or Early Termination.  Clinical 
laboratory values may be repeated prior to randomization in order to confirm exclusionary levels 
for TSH, ALT and/or AST values.  If these values remain persistently elevated upon repeat, the 
patient is not eligible for randomization. 
With the exception of the urine pregnancy tests or the ad hoc urine drug test required at baseline 
for patients washing off excluded medications (e.g., opioids, benzodiazepines, amphetamines), 
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. 
A urine drug screen for drugs of abuse (including marijuana) will be collected at Screening 
Visit 1 and sent to the central laboratory for analysis.  If the patient has a positive drug screen at 
Visit 1 and/or Visit 2 for anything other than marijuana, and the results cannot be explained by 
use of current allowable prescription medications, the patient should be excluded from the study.  
If the urine drug screen is positive at Visit 1 and the results can be explained by the use of 
current prescription medications (e.g., opioids, benzodiazepines, amphetamines) that will be 
discontinued during screening, the investigator must repeat the drug screen and obtain a negative 
result using an in-clinic urine dipstick drug screen prior to randomization to confirm eligibility 
for the study. 
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 
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Table 2: 
Clinical Laboratory Assessments 
Clinical chemistry 
Hematology 
Alanine aminotransferase (ALT)a  
Hematocrit 
Alkaline phosphatase 
Hemoglobin 
Aspartate aminotransferase (AST)a  
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 
 
Thyroid-stimulating hormone (TSH) c at 
screening 
Serum Pregnancy Test at Screeningb 
Free T4 only if TSH is outside of normal limits 
Urine Pregnancy Test (qualitative dipstick)b 
Human immunodeficiency virus types 1 and 2 
(HIV1 and HIV2) 
Urine Drug Screend 
Pharmacogenomic testing for invited 
participants at 5 study sites (optional) 
(Separate Visit post Week 12/ET) 
 
a  Level greater than 3 times the upper limit of normal is an exclusion (if persistent upon repeat). 
b Pregnancy testing for females of child-bearing potential only.  A positive pregnancy test is exclusionary (Visit 1 or Visit 2) or mandates 
withdrawal from the study (all other visits). 
c TSH level greater than 1.5 times higher than the upper limit of normal is exclusionary at Visit 1. 
d Urine drug screening will be conducted on all patients at Screening and, if necessary, at Baseline in patients with a positive result at Screening 
who otherwise qualify for the study.  For patients testing positive at the Screening visit for an excluded medication that will be discontinued 
during the screening interval, an in-clinic urine dipstick drug screen will be performed at the Baseline visit and must be negative for opioids, 
benzodiazepines, amphetamines and illicit drugs other than marijuana in order for the patient to be eligible for randomization. 
11.3.9. 
Assessment of Changes in Sexual Function: Changes in Sexual Functioning 
Questionnaire Short-Form (CSFQ-14) 
The Changes in Sexual Functioning Questionnaire Short-Form (CSFQ-14) (Keller et al. 2006) is 
validated scale with internal reliability designed to allow a patient to self-evaluate his or her 
sexual behaviors or problems in a number of areas.  The CSFQ-14 will be administered at 
Baseline (Visit 2) and Week 12/ET (Visit 6).  It yields a total score, three subscales 
corresponding to phases of the sexual response cycle (i.e. desire, arousal, orgasm), and five 
subscales corresponding to important dimensions of sexual functioning.  It is considered a useful 
scale for assessing sexual side effects of medications.  For all items, higher scores reflect higher 
sexual functioning.  For 12 of the 14 items, higher sexual functioning corresponds to greater 


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frequency or enjoyment/pleasure (e.g. 1=never to 5 = every day).  For two items (item 10, 
assessing loss of interest after arousal for women and priapism for men, and item 14, assessing 
painful orgasm), higher sexual functioning corresponds to lower frequency (e.g. 1=every day to 
5=never). Items 10 and 14 are included in the total score but not in any scale score. 
11.3.10. 
Assessment of Sedation:  Morning Treatment-Related Sedation Score (MTRSS) 
The Morning Treatment-Related Sedation Score (MTRSS) is designed to assess the patient’s 
morning sedation at clinic visits.  The MTRSS will be assessed at Baseline (Visit 2) and at 
Weeks 4, 8, and 12/ET (Visits 4, 5, and 6).  The patient will complete the following questions: 
A.  On most mornings during the past week, I have awakened feeling: 
0. Alert with no grogginess 
1. Mildly groggy 
2. Moderately groggy 
3. Very groggy 
B. If you reported any grogginess in the last week (responses 1-3), the grogginess lasted: 
1. A few minutes 
2. A short time (less than one hour) 
3. A long time (more than one hour) 
Note: if “Alert with no grogginess is selected in Part A, Part B is not answered, and the score for 
part B is 0. 
 
11.4. 
Pharmacogenomic Assessment 
For pharmacogenomic analysis, a single blood sample collected in one PAXgene DNA tube will 
be obtained from an invited group of patients at 5 study sites after participation in the main study 
has ended.  Patients had to have received active drug during the main study, at least one CAPS-5 
assessment post-Baseline, and the patient has provided separate written, signed informed consent 
for pharmacogenomic analysis. The blood sample will be sent by the site to the 
pharmacogenomics testing laboratory where first DNA is extracted from the whole blood 
sample, and subsequently exome sequencing is performed on the DNA. The purpose of this 
testing is to allow exome sequencing and analysis for genetic variants related to treatment 
response and presence or absence of adverse events to TNX-102 SL.  
12. 
DEFINITIONS, RECORDING, AND REPORTING OF ADVERSE 
EVENTS 
12.1. 
Definition of Adverse Events 
According to International Conference on Harmonization (ICH) guidance E2A, Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting, an adverse event (AE) is 


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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 treatment-emergent AE (TEAE) is an AE that either commenced following initiation of study 
treatment or was present prior to study treatment but increased in frequency or severity following 
initiation of study treatment. 
12.2. 
Adverse Event Recording 
12.2.1. 
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. 
12.2.2. 
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 patient 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 patient’s normal daily activities and generally require 
systemic drug therapy or other treatment; they are usually incapacitating. 
To make sure there is no confusion or misunderstanding of the difference between the terms 
“serious “and “severe,” which are not synonymous, the following note of clarification is 
provided.  The term “severe” is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe myocardial infarction); the event itself, however, maybe of 
relatively minor medical significance (such as severe headache).  This is not the same as 
“serious,” which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient's life or functioning.  Seriousness (not severity) serves as a 
guide for defining regulatory reporting obligations. 
12.2.3. 
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 


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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. 
12.3. 
Serious Adverse Events (SAEs) and Serious Adverse Drug Reactions 
Any SAE that occurs at any time during the study, 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 facsimile and 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 1 working day 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 or dosage. 
A serious adverse event (experience) or reaction is any untoward medical occurrence that, at any 
dose: 
• Results in death, 
• Is life-threatening, 
• Requires in-patient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, 
• Is a congenital anomaly/birth defect, or 
• Is an important medical event 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event.  It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These should 
also usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
A death occurring during the study, during the per-protocol follow-up period, 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 






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13.3. 
Assessment of Demographic and Baseline Characteristics 
Demographic and baseline characteristics such as age, gender, race/ethnicity, height, weight, 
BMI, presence of current major depressive episode, family status, education, employment status, 
and smoking history will be summarized by treatment group (TNX-102 SL and placebo) and 
overall using descriptive statistics. 
Medical History will be coded using MedDRA and summarized by SOC and Preferred Term 
using frequency counts by treatment group. 
13.4. 
Efficacy Analysis 
13.4.1. 
Efficacy Endpoints 
Primary Efficacy Endpoint: 
The mean change from baseline (Visit 2) in the Total CAPS-5 score after 12 weeks of treatment 
evaluated at Visit 6. 
Secondary Efficacy Endpoints: The first two secondary efficacy endpoints listed below are 
considered key secondary endpoints and will be tested in that order. 
• CGI-I score (analyzed as a continuous variable) after 12 weeks of treatment. 
• Change from baseline in the SDS total score after 12 weeks of treatment. 
Other Secondary Efficacy Endpoints:  
• Change from baseline in patients’ quality of sleep using the PROMIS Sleep 
Disturbance scale after 12 weeks of treatment. 
• Change from baseline in the disruption of work/school activities assessed using the 
SDS after 12 weeks of treatment. 
• Change from baseline in disruption of social life/ leisure activities assessed using the 
SDS after 12 weeks of treatment. 
• Change from Baseline in the disruption of family life/home responsibilities assessed 
using the SDS after 12 weeks of treatment. 
• Change from baseline in CAPS-5 Arousal and Reactivity (Criterion E) score after 12 
weeks of treatment. 
• Change from baseline in CAPS-5 Intrusion symptoms (Criterion B) score after 12 
weeks of treatment. 
• Change from baseline in CAPS-5 Persistent Avoidance (Criterion C) score after 12 
weeks of treatment. 
• Change from baseline in CAPS-5 Negative Cognition and Mood (Criterion D) score 
after 12 weeks of treatment. 
• Change from baseline in CAPS-5 Sleep Disturbance (item E-6) score after 12 weeks 
of treatment. 


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• Change from baseline in CAPS-5 Exaggerated Startle (item E-4) score after 12 weeks 
of treatment.  
• PGIC score after 12 weeks of treatment. 
• Proportion of patients with a PGIC score of “much improved” or “very much 
improved” after 12 weeks of treatment 
• Proportion of patients with a treatment response on the CGI-I defined as a CGI-I 
score of “much improved” or “very much improved” after 12 weeks of treatment. 
• Proportion of patients with a Total CAPS-5 score of 0 –10 (asymptomatic/few 
symptoms) after 12 weeks of treatment. 
• Proportion of patients with a Total CAPS-5 score of 0 -22 (asymptomatic or mild 
PTSD/subthreshold) after 12 weeks of treatment. 
• Proportion of patients with Response, defined as a ≥ 10-point improvement from 
baseline in Total CAPS-5 score after 12 weeks of treatment. 
• Proportion of patients with Loss of Diagnosis, defined as Response AND no longer 
meeting DSM-5 symptom criteria in any one or more of the four clusters (B, C, D, E) 
after 12 weeks of treatment. 
• Proportion of patients in Remission, defined as Loss of Diagnosis AND Total CAPS-
5 score ≤ 10 after 12 weeks of treatment.   
• Proportion of patients achieving sustained Remission, defined as Loss of Diagnosis 
AND Total CAPS-5 score ≤ 10 after 8 weeks AND 12 weeks of treatment. 
• Proportion of patients with a ≥50% improvement from baseline in Total CAPS-5 
score after 12 weeks of treatment. 
• Change from baseline in BDI-II score after 12 weeks of treatment. 
• Change from baseline in CAPS-5 Reckless or Self-Destructive Behavior (item E-2) 
score after 12 weeks of treatment.  
 
Exploratory Endpoints:  Any exploratory endpoints will be delineated in the SAP.   
13.4.2. 
Primary Efficacy Analysis 
The primary efficacy analysis will use a mixed model repeated measures (MMRM) approach to 
estimate mean change from baseline in the Total CAPS-5 score evaluated after 12 weeks of 
treatment in the TNX-102 SL 5.6 mg and placebo arms.  The model will include all patients in 
the mITT population, and the dependent variable will be the observed change from baseline in 
total CAPS-5 score at each post-randomization visit.  Covariates in the model will include the 
fixed categorical effects of treatment, site, sex, current tobacco use status, presence of current 
MDE, visit and treatment by visit interaction, as well as the continuous fixed covariates of 
baseline score and baseline score by visit interaction.  Missing data will be imputed via multiple 
imputation (MI), and details regarding the MI approach will be described in the SAP.   


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The primary analysis will be followed by several sensitivity analyses.  Further details on 
sensitivity analyses can be found in the SAP. 
13.4.3. 
Secondary Efficacy Analyses 
MMRM methodology will be utilized for the continuous secondary endpoints, and analyses will 
be based on the mITT population.  The dependent variable will be the observed change from 
baseline in the respective secondary endpoint at each post-randomization visit, with the 
exception of the CGI-I which does not have a baseline.  Covariates in the model will include the 
fixed categorical effects of treatment, site, sex, current tobacco use status, presence of current 
MDE, visit and treatment by visit interaction (baseline score and baseline score by visit 
interaction will be included as appropriate).   
Binary data will be analyzed using a Cochran-Mantel-Haenszel test controlling for the 
randomization stratification of presence of current MDE, analyzed separately at each visit.  
Patients with missing data will be analyzed as though they are non-responders. The primary time 
point of interest will be Week 12.  Odds ratios and corresponding 95% confidence intervals will 
be presented. 
To adjust for multiplicity and to control for overall type I error, a sequential test procedure will 
be applied to the key secondary efficacy endpoints.  If the primary analysis produces a result that 
is statistically significant, a nominal significance level will be used for comparing the secondary 
endpoints in an ordered fashion.  If the analysis for a secondary endpoint does not produce a 
statistically significant result, then the remaining secondary endpoint analyses will automatically 
be considered non-significant regardless of the p-value produced.  In the case of an early stop or 
increase in sample size, the same methodology/critical value used for the primary endpoint will 
be applied to the key secondary endpoints for the purposes of the sequential testing.  See the SAP 
for additional details. 
The testing order for the two key secondary endpoints is as follows: 
• CGI-I score (analyzed as a continuous variable) after 12 weeks of treatment. 
• Change from baseline in the SDS total score after 12 weeks of treatment. 
No other adjustments for multiplicity will be made and other p-values displayed in the output 
will be considered for descriptive summary purposes only and will not be used for formal 
inference.  Full details regarding the statistical analyses for the listed endpoints will be provided 
in the SAP. 
13.4.4. 
Exploratory Analyses 
Exploratory efficacy analyses will be based on the mITT population.  Details on exploratory 
efficacy analyses can be found in the SAP. 
13.5. 
Safety Analyses 
Safety will be assessed by: 
• Adverse events and serious AEs throughout the entire duration of the study, including 
assessment of AEs involving the oral cavity 


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• Changes from baseline in clinical laboratory test results 
• Changes from baseline in vital signs and weight 
• Changes from baseline indicative of increased suicidal ideation or behavior as 
assessed by the C-SSRS 
• Changes from baseline in BDI-II 
• Changes from baseline in patient-rated sexual function as assessed by the CSFQ-14 
• Changes from baseline in patient-rated morning sedation as assessed by the MTRSS 
Adverse events will be coded using the latest version of 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 Baseline for clinical 
laboratory test results, MTRSS scores, CSFQ-14 scores, BDI-II scores, and vital sign 
measurements will be summarized at endpoint using descriptive statistics (n, mean, SD, median, 
minimum, and maximum). 
The number of patients with suicidal behaviors, ideations and acts based on the C-SSRS will be 
tabulated by treatment group and listed. 
13.6. 
Interim Analyses 
One planned interim analysis for the purposes of sample size reassessment and to assess stopping 
early for either futility or success will be performed.  The interim analysis will be conducted 
when approximately 50% of the total planned enrollment is evaluable for efficacy. 
An adaptive group sequential design will be used for early efficacy testing.  The details of this 
testing will be described in an ISAP, which will be finalized prior to the interim analysis. 
The interim analysis will be performed by an independent unblinded statistical group.  Results of 
this assessment will be provided to an Independent Data Monitoring Committee (IDMC).  The 
IDMC Charter will outline the roles and responsibilities of the IDMC as well as the interim 
analysis decision rules.   
The following recommendations can be made at the time of the interim analysis: The IDMC will 
inform the Sponsor to increase the sample size by a fixed amount, keep the current sample size 
and continue, stop the study for futility, or stop the study early for success.  If the study is 
stopped early for success based on the interim analysis results, currently randomized patients 
who have not yet completed the study will be offered an immediate transition into an open-label 
extension safety study (Protocol No. TNX-CY-P306). 


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14. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY 
14.1. 
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. 
14.2. 
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. 
15. 
ETHICAL CONSIDERATIONS 
15.1. 
Ethical Conduct of the Study 
This protocol is written in accordance with the principles established by the 18th World Medical 
Assembly General Assembly (Helsinki, 1964) 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 


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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. 
15.2. 
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. 
15.3. 
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 serotoninergic medications (e.g., triptans) 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.  Patients on MAOIs should not be 
considered for the study, and MAOIs should not be initiated during the study due to the 
additional safety concerns posed by this class of medication when used in combination with 
other serotoninergic drugs (such as cyclobenzaprine). 
The patient should also be asked in the Informed Consent Form (ICF) for permission for the 
principal investigator or his designee to contact the patient’s other personal physicians, as 
appropriate, concerning participation in the study. Separate written, signed informed consent 
must be obtained if the patient is to participate in the post-study optional pharmacogenomic 
assessment. 
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with International Conference on Harmonization (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 


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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. 
16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
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.  Investigator 
can use the Certificate to avoid compelled "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. 
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 


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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. 
16.3. 
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 
investigator will assume the responsibility of ensuring the completeness and accuracy of the 
clinical data.  All data will be verified for quality control and will also be patient to audits from 
Tonix or designee to ensure quality. 
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. 
16.4. 
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. 
16.5. 
Screening Records 
A record generated by IWRS 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. 


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16.6. 
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. 
16.7. 
Site Monitoring and Tonix’s Right to Review Records 
Monitoring and auditing procedures developed by Tonix and/or its designee will be implemented 
to ensure compliance with FDA and ICH GCP and GLP guidelines. 
Tonix’s designated representative (the monitor or auditor) will contact the investigator and 
conduct regular visits to the clinical site.  The monitor will be expected and allowed to verify the 
investigator’s qualifications, to inspect clinical site facilities, and to inspect study records, 
including proof of EC/IRB review, with the stipulation that patient confidentiality will be 
maintained in accordance with local and federal regulations, including HIPAA requirements.  
The monitor will also be responsible for confirming adherence to the study protocol, inspecting 
CRFs and source documents, and ensuring the integrity of the data.  CRFs will be checked for 
accuracy, completeness, and clarity and will be cross-checked for consistency with source 
documents, including laboratory test reports and other patient records.  Instances of missing or 
uninterpretable data will be resolved in coordination with the investigator. 
The monitor/auditor will also investigate any questions concerning adherence to regulatory 
requirements.  Any administrative concerns will be clarified and followed.  The monitor will 
maintain contact with the site through frequent direct communications with the study site by e-
mail, telephone, facsimile, and mail.  The investigator and all other site personnel agree to 
cooperate fully with the monitor and will work in good faith with the monitor to resolve any and 
all questions raised and difficulties detected by the monitor. 
16.8. 
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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17. 
CONFIDENTIALITY 
17.1. 
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 enroll in the study.  Investigators 
can use the Certificate to avoid compelled "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. 
17.2. 
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. 
17.3. 
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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18. 
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Barnes CD, Fung SJ, Gintautas J.  Brainstem noradrenergic system depression by 
cyclobenzaprine.  Neuropharmacology 1980 Feb; 19 (2):221-224. 
Berridge CW, Schmeichel BE, Espãna RA.  Noradrenergic modulation of wakefulness/arousal. 
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Betts KS, Williams GM, Najman JM, Alati R.  The role of sleep disturbance in the relationship 
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41. 
Breslau N, Roth T, Burduvali E, Kapke A, Schultz L, Roehrs T. Sleep in lifetime posttraumatic 
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61(5):508-516. Erratum in: Arch Gen Psychiatry 2005 Feb; 62(2):172. 
Capaldi VF 2nd, Guerrero ML, Killgore WD. Sleep disruptions among returning combat 
veterans from Iraq and Afghanistan. Mil Med 2011 Aug; 176 (8):879-888. 
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Davidson JR, Weisler RH, Butterfield MI, Casat CD, et al. Mirtazapine vs. placebo in 
posttraumatic stress disorder: A pilot trial.  Biol Psychiatry 2003 Jan 15; 53(2):188-191. 
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Germain A. Sleep disturbances as the hallmark of PTSD: Where are we now? Am J Psychiatry 
2013; 170:372-382. 
Halász P1, Terzano M, Parrino L, Bódizs R. The nature of arousal in sleep. J Sleep Res 2004; 
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Hertzberg MA, Feldman ME, Beckham JC, Davidson JR.  Trial of trazodone for posttraumatic 
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Hidalgo R, Hertzberg MA, Mellman T, Petty F, et al. Nefazodone in post-traumatic stress 
disorder: Results from six open-label trials.  Int Clin Psychopharmacol 1999 Mar; 14(2):61-68. 
Hoge, C. W., McGurk, D., Thomas, J.L., Cox, A.L., Engel, C.C. & Castro, C.A. Mild traumatic 
brain injury in US soldiers returning from Iraq. New England Journal of Medicine 2008; 358, 
453–463. 
Honda M, Nishida T, Ono H.  Tricyclic analogs cyclobenzaprine, amitriptyline and 
cyproheptadine inhibit the spinal reflex transmission through 5-HT(2) receptors.  Eur J 
Pharmacol 2003 Jan 1; 458(1-2):91-99. 
Huang ZL, Mochizuki T, Qu WM, Hong ZY, Watanabe T, Urade Y, Hayaishi O. Altered sleep-
wake characteristics and lack of arousal response to H3 receptor antagonist in histamine H1 
receptor knockout mice. Proceedings of the National Academy of Sciences of the United States 
of America. 2006;103:4687-4692. 
Keller A, McGarvey EL, Clayton AH. Reliability and construct validity of the changes in sexual 
functioning questionnaire Short form (CSFQ-14). J of Sex and Marital Ther. 2006; 32:43-52. 
Kelly UA, Skelton K, Patel M, Bradley B. More than military sexual trauma: interpersonal 
violence, PTSD, and mental health in women veterans. Res Nurs Health. 2011;34:457-467. 
Kim W, Pae CU, Chae JH, Jun TY, Bahk WM.  The effectiveness of mirtazapine in the treatment 
of post-traumatic stress disorder: a 24-week continuation therapy.  Psychiatry Clin Neurosci 
2005 Dec; 59(6):743-747. 
Kobayashi H, Hasegawa Y, Ono H.  Cyclobenzaprine, a centrally acting muscle relaxant, acts on 
descending serotonergic systems.  Eur J Pharmacol 1996 Sep 5; 311(1):29-35.  
Kobayashi I, Boarts JM, Delahanty DL. Polysomnographically measured sleep abnormalities in 
PTSD: A meta-analytic review. Psychophysiology 2007; 44(4):660-669. 
Koren D, Arnon I, Lavie P, Klein E.  Sleep complaints as early predictors of posttraumatic stress 
disorder: A 1-year prospective study of injured survivors of motor vehicle accidents.  Am J 
Psychiatry 2002 May; 159(5):855-857. 
Krakow B, Artar A, Warner TD, Melendrez D, et al.  Sleep disorder, depression, and suicidality 
in female sexual assault survivors.  Crisis 2000; 21(4):163-170. 
Krakow B, Melendrez D, Johnston L, Warner TD, et al.  Sleep-disordered breathing, psychiatric 
distress, and quality of life impairment in sexual assault survivors.  J Nerv Ment Dis 2002 Jul; 
190(7):442-452. 
Krakow B, Melendrez D, Pedersen B, Johnston L, et al.  Complex insomnia: Insomnia and sleep-
disordered breathing in a consecutive series of crime victims with nightmares and PTSD.  Biol 
Psychiatry 2001; 49(11):948-953. 
Krystal AD, Zhang W, Davidson JR, Connor KM.  The sleep effects of tiagabine on the first 
night of treatment predict post-traumatic stress disorder response at three weeks.  J 
Psychopharmacol 2013; Nov 28 [epub ahead of print]. 
Lewis JD.  Mirtazapine for PTSD nightmares.  Am J Psychiatry 2002 Nov; 159(11):1948-1949. 


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Llorca PM, Spadone C, Sol O, Danniau A, Bougerol T, Corruble E, Faruch M, Macher JP, 
Sermet E, Servant D. Efficacy and safety of hydroxyzine in the treatment of generalized anxiety 
disorder: a 3-month double-blind study. J Clin Psychiatry. 2002;63:1020-1027. 
Maren S, Phan KL, Liberzon I. The contextual brain: implications for fear conditioning, 
extinction and psychopathology. Nat Rev Neurosci. 2013;14:417-428. 
McLay RN, Klam WP, Volkert SL.  Insomnia is the most commonly reported symptom and 
predicts other symptoms of post-traumatic stress disorder in U.S. service members returning 
from military deployments.  Mil Med 2010; 175(10):759-762. 
Mellman TA, Bustamante V, Fins AI, Pigeon WR, Nolan B.  REM sleep and the early 
development of posttraumatic stress disorder.  Am J Psychiatry 2002 Oct; 159(10):1696-1701. 
Mellman TA, David D, Kulick-Bell R, Hebding J, Nolan B. Sleep disturbance and its 
relationship to psychiatric morbidity after Hurricane Andrew. Am J Psychiatry. 1995;152:1659-
1663. 
Moldofsky H, Harris HW, Archambault WT, Kwong T, Lederman S.  Effects of bedtime very 
low dose cyclobenzaprine on symptoms and sleep physiology in patients with fibromyalgia 
syndrome: A double-blind randomized placebo-controlled study.  J Rheumatol 2011; 38(10):1-
11. 
Monti JM. Serotonin control of sleep-wake behavior. Sleep Med Rev. 2011;15:269-281. 
Neylan TC, Lenocil M, Maglione ML, Rosenlicht NZ, et al. Delta Sleep Response to 
Metyrapone in Post-Traumatic Stress Disorder. Neuropsychopharmacology 2003; 28: 1666–
1676. 
Neylan TC, Marmar CR, Metzler TJ, Weiss DS, Zatzick DF, Delucchi KL, Wu RM, Schoenfeld 
FB. Sleep disturbances in the Vietnam generation: findings from a nationally representative 
sample of male Vietnam veterans. Am J Psychiatry. 1998;155:929-933. 
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Psychiatry 2003; 160(3):580-2. 
Pace-Schott EF, Germain A, Milad MR. Sleep and REM sleep disturbance in the 
pathophysiology of PTSD: the role of extinction memory. Biol Mood Anxiety Disord. 2015;5:3. 
Pace-Schott EF, Milad MR, Orr SP, Rauch SL, Stickgold R, Pitman RK. Sleep promotes 
generalization of extinction of conditioned fear. Sleep. 2009;32:19-26. 
Pietrzak RH, Morgan CA, 3rd, Southwick SM. Sleep quality in treatment-seeking veterans of 
Operations Enduring Freedom and Iraqi Freedom: the role of cognitive coping strategies and unit 
cohesion. J Psychosom Res. 2010;69:441-448. 
Raskind MA, Peskind ER, Hoff DJ, Hart KL, et al.  A parallel group placebo controlled study of 
prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic 
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Serafim KR, Gianlorenco AC, Daher FP, Mattioli R. H1-histamine receptors in the amygdala are 
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Serafim KR, Kishi MS, Canto-de-Souza A, Mattioli R. H(1) but not H(2) histamine antagonist 
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19. 
APPENDICES 
APPENDIX 1. STUDY DESIGN AND SCHEDULE OF ASSESSMENTS 
Period 
Screening 
Baseline 
Double-Blind Treatment Period 
Post-
Study 
Visit 
1 
2 
3a 
4 
5 
6 
7 
Study Week 
-5 to -1  
0 
2 
4 
8 
12 
 
Study Day 
-35 to -7 
0 
14 ± 3  
28± 5 
56 ± 5 
84 -5/+7 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria  
X 
X 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
Psychiatric History 
(M.I.N.I. 7.0.2)  
X 
 
 
 
 
 
 
Demographics and 
Medical History  
X 
Xb 
 
 
 
 
 
Prior and Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
 
Vital Signs, heightc, 
weight and BMI  
X 
X 
 
X 
X 
X 
 
Physical Examination  
X 
 
 
 
 
 
 
Inspection of oral cavity 
X 
Xd 
 
 
 
X 
 
12-Lead 
Electrocardiogram  
X 
 
 
 
 
 
 
Pregnancy Teste 
Xf 
X 
 
X 
X 
Xf 
 
Urine Drug Screen  
X 
Xg 
 
 
 
 
 
Clinical Laboratory 
Assessmentsh 
X 
 
 
 
 
X 
 
HIV, and TSH  
X 
 
 
 
 
 
 
Beck Depression 
Inventory (BDI-II) 
X 
X 
 
X 
X 
X 
 
LEC-5  
X 
 
 
 
 
 
 
CA-AF 
X 
 
 
 
 
 
 
CAPS-5  
Xi 
Xj, k 
 
Xk 
Xk 
Xk 
 
C-SSRS 
Xl 
Xm 
Xm 
Xm 
Xm 
Xm 
 
CGI-I 
 
 
 
X 
X 
X 
 
PGIC 
 
 
 
X 
X 
X 
 
PROMIS-sleep (short 
form) 
 
X 
 
X 
X 
X 
 
CSFQ-14 
 
X 
 
 
 
X 
 
MTRSS 
 
X 
 
X 
X 
X 
 
SDS 
 
X 
 
X 
X 
X 
 


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Period 
Screening 
Baseline 
Double-Blind Treatment Period 
Post-
Study 
Visit 
1 
2 
3a 
4 
5 
6 
7 
Study Week 
-5 to -1  
0 
2 
4 
8 
12 
 
Study Day 
-35 to -7 
0 
14 ± 3  
28± 5 
56 ± 5 
84 -5/+7 
 
Adverse Events 
 
X 
X 
X 
X 
X 
 
Telephone Visita 
 
 
X 
 
 
 
 
Dispense Study Drugn 
 
X 
 
X 
X 
 
 
Collect/ Count Study 
Drug Returned 
 
 
 
X 
X 
X 
 
Informed Consent for 
Pharmacogenomic blood 
draw o 
 
 
 
 
 
 
X 
Pharmacogenomic blood 
draw (optional) o 
 
 
 
 
 
 
X 
 
Abbreviations:  BDI-II = Beck Depression Inventory; BMI = Body Mass Index; CA-AF = Criterion A – 
Assessment Form; CAPS-5 = Clinician Administered PTSD Scale (for DSM-5); CSFQ-14=Changes in Sexual 
Functioning Questionnaire Short-Form; C-SSRS = Columbia-Suicide Severity Rating Scales; HIV = Human 
immunodeficiency virus; LEC-5 = Life Events Checklist for DSM-5; M.I.N.I = Mini International Neuropsychiatric 
Interview; MTRSS = Morning Treatment-Related Sedation Scale; PGIC = Patient Global Impression of Change; 
PROMIS = Patient Reported Outcomes Measurement Information System; SDS = Sheehan Disability Scale; 
TSH=Thyroid Stimulating Hormone;  
a Week 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. 
b Only updates from screening 
c Height to be measured at Visit 1 only 
d 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. 
e Women of child-bearing potential only 
f Serum pregnancy test required at Visit 1 only; all other pregnancy tests via urine dipstick performed in 
the clinic. Serum pregnancy test at Visit 6/Early Termination may be done at Investigator’s discretion. 
g Urine dipstick to confirm eligibility if Visit 1 results were positive for excluded medication requiring 
washout 
h  Chemistry and hematology 
i  Visit 1 CAPS-5 will utilize the “Diagnostic Version” (past month recall). Patients must meet criteria for 
diagnosis of PTSD and have a total score ≥33 
j  Total CAPS-5 score must be ≥33(“Symptom Severity Version” using 1-week recall) 
k CAPS-5 “Symptom Severity Version” using 1-week recall 
l C-SSRS (“Baseline/Screening” Version) 


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m C-SSRS (“Since Last Visit” Version) 
n Four-week supply of study medication will be dispensed at each dispensing visit. Must access IWR 
system in order to obtain correct bottle number to dispense 
oThe blood draw for the pharmacogenomic assessment will be obtained post study participation for an 
invited group of patients at 5 study sites. Separate written, signed informed consent is required if the 
patient is to participate in the optional pharmacogenomic assessment.  
 
 
 
 


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


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


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TABLE OF CONTENTS 
DOCUMENT HISTORY ..................................................................................................2 
TABLE OF CONTENTS ..................................................................................................4 
ABBREVIATIONS ............................................................................................................7 
1. 
OVERVIEW ...........................................................................................................9 
2. 
STUDY OBJECTIVES AND ENDPOINTS ......................................................10 
2.1 
Study Objectives ........................................................................................10 
2.1.1 Primary Objective ..........................................................................10 
2.1.2 Secondary Objectives.....................................................................10 
2.2 
Study Endpoints .........................................................................................10 
2.2.1 Efficacy Endpoints .........................................................................10 
2.2.2 Exploratory Efficacy Endpoints .....................................................12 
2.2.3 Safety Endpoints ............................................................................12 
3. 
OVERALL STUDY DESIGN AND PLAN .......................................................13 
3.1 
Selection of Study Population ....................................................................13 
3.2 
Method of Treatment Assignment and Randomization .............................13 
3.3 
Treatment Blinding ....................................................................................14 
3.4 
Minimization of Missing Data / Dropout rate............................................14 
4. 
ANALYSIS AND REPORTING ........................................................................16 
4.1 
Interim Analysis .........................................................................................16 
4.2 
Final Analysis ............................................................................................16 
5. 
SAMPLE SIZE DETERMINATION .................................................................17 
6. 
ANALYSIS POPULATIONS .............................................................................18 
7. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ..................................19 
7.1 
General Statistical Methodology................................................................19 
7.1.1 Adjustments for Multiplicity and Other Alpha Control .................19 
7.1.2 Data Handling for Participants Who Discontinue Study Drug or 
Withdraw from the Study...............................................................20 
7.2 
Efficacy Assessments.................................................................................20 
7.2.1 Primary Efficacy ............................................................................21 
7.2.2 Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) ..........21 
7.2.3 Key Secondary Efficacy Assessments ...........................................22 
7.2.4 Other Efficacy Outcomes ...............................................................23 


 
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7.3 
Safety Assessments ....................................................................................24 
7.3.1 Adverse Event and Prior/Concomitant Medication handling 
conventions ....................................................................................24 
8. 
STUDY PARTICIPANTS AND DEMOGRAPHICS .......................................26 
8.1 
Disposition of Participants and Withdrawals .............................................26 
8.2 
Protocol Deviations ....................................................................................26 
8.3 
Demographics and Other Baseline Characteristics ....................................26 
9. 
EFFICACY ANALYSES ....................................................................................27 
9.1 
Primary Efficacy Analysis Approach ........................................................27 
9.1.1 Primary Efficacy Analysis .............................................................27 
9.1.2 Sensitivity and Supporting Analyses .............................................29 
9.1.3 Graphical Representations .............................................................29 
9.2 
Secondary Efficacy Analysis .....................................................................30 
9.2.1 Continuous outcomes .....................................................................30 
9.2.2 Categorical outcomes .....................................................................31 
10. 
SAFETY AND TOLERABILITY ANALYSIS .................................................32 
10.1 
Adverse Events ..........................................................................................32 
10.1.1 Adverse Events Leading to Discontinuation of Study Drug ..........33 
10.1.2 Serious Adverse Events .................................................................33 
10.1.3 Deaths ............................................................................................33 
10.2 
Clinical Laboratory Evaluations ................................................................33 
10.3 
Columbia Suicide Severity Rating Scale (C-SSRS) ..................................33 
10.4 
Vital Signs ..................................................................................................34 
10.5 
Physical Examination and Visual Examination of Oral Cavity .................34 
10.6 
Electrocardiogram (ECG) ..........................................................................35 
10.7 
Assessment of Sedation Morning Treatment-Related Sedation Score 
(MTRSS) ....................................................................................................35 
10.8 
Assessment of Changes in Sexual Function: Changes in Sexual Functioning 
Questionnaire Short-Form (CSFQ-14) ......................................................35 
11. 
MEDICATIONS ..................................................................................................37 
11.1 
Concomitant Medication ............................................................................37 
11.2 
Exposure and Compliance .........................................................................37 
12. 
CHANGES FROM PLANNED ANALYSIS .....................................................38 
13. 
REFERENCES .....................................................................................................39 


 
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14. 
APPENDICES ......................................................................................................40 
14.1 
Appendix 1 .................................................................................................40 
14.1.1 General Reporting Conventions .....................................................40 
14.1.2 Population Summary Conventions ................................................41 
14.2 
Appendix 2: PROMIS T-score Conversions..............................................42 
14.3 
Appendix 3: Seeds for Imputation: ............................................................43 
 


 
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ABBREVIATIONS 
ABBREVIATION DEFINITION OR DESCRIPTION 
AE 
Adverse Event 
ADaM 
Analysis Data Model 
BDI-II 
Beck Depression Inventory–II 
BMI 
Body Mass Index 
CA-AF 
Criterion A – Assessment Form 
CAPS-5 
Clinician Administered PTSD Scale (for DSM-5) 
CGI-I 
Clinical Global Impression- Improvement from Initiation of Treatment 
CI 
Confidence Interval 
CMH 
Cochran Mantel Haenszel 
CRF 
Case Report Form 
CRO 
Contract Research Organization  
CSFQ-14 
Changes in Sexual Functioning Questionnaire Short Form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders (Version 4) 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders (Version 5) 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
e.g. 
Exempli gratia (for example) 
EMA 
European Medicines Agency 
ET 
Early Termination 
FDA 
Food and Drug Administration 
HCl 
Hydrochloride 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
i.e. 
id est (that is) 
ISAP 
Interim Statistical Analysis Plan 
IWRS 
Interactive Web Response System 
LEC-5 
Life Events Checklist for DSM-5 
LS 
Least Squares 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MDE 
Major Depressive Episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
Military-Related 
Related to service in any branch of the armed services (active or veteran), 
or as a military contractor 
MI 
Multiple Imputation 
MINI 
Mini International Neuropsychiatric Interview 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing Not at Random 
MTRSS 
Morning Treatment-Related Sedation Scale 


 
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N, n 
Number (of participants) 
NIH 
National Institutes of Health 
PGIC 
Patient Global Impression of Change Scale 
PROMIS 
Patient-Reported Outcome Measurement Information System 
PTSD 
Posttraumatic Stress Disorder 
REML 
Restricted Maximum Likelihood 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SD 
Standard deviation 
SDS 
Sheehan Disability Scale 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SL 
Sublingual 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TNX-102 SL  
Cyclobenzaprine HCl sublingual tablets 
WHO-DD 
World Health Organization Drug Dictionary 
 






 
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• Change from baseline in disruption of social life/ leisure activities assessed 
using the SDS after 12 weeks of treatment. 
• Change from baseline in the disruption of family life/home responsibilities 
assessed using the SDS after 12 weeks of treatment. 
• Change from baseline in CAPS-5 Arousal and Reactivity (Criterion E) score 
after 12 weeks of treatment. 
• Change from baseline in CAPS-5 Intrusion symptoms (Criterion B) score after 
12 weeks of treatment. 
• Change from baseline in CAPS-5 Persistent Avoidance (Criterion C) score 
after 12 weeks of treatment. 
• Change from baseline in CAPS-5 Negative Cognition and Mood (Criterion D) 
score after 12 weeks of treatment. 
• Change from baseline in CAPS-5 Sleep Disturbance (item E-6) score after 12 
weeks of treatment. 
• Change from baseline in CAPS-5 Exaggerated Startle (item E-4) score after 
12 weeks of treatment.  
• Patient Global Impression of Change Scale (PGIC) score after 12 weeks of 
treatment. 
• Proportion of participants with a PGIC score of “much improved” or “very 
much improved” after 12 weeks of treatment. 
• Proportion of CGI-I Responders, defined as a CGI-I score of 2 (“much 
improved”) or 1 (“very much improved”), after 12 weeks of treatment.  
• Proportion of participants with a Total CAPS-5 score of 0 –10 
(asymptomatic/few symptoms) after 12 weeks of treatment. 
• Proportion of participants with a Total CAPS-5 score of 0-22 (asymptomatic 
or mild PTSD/subthreshold) after 12 weeks of treatment. 
• Proportion of participants with Response, defined as a ≥ 10-point 
improvement from baseline in Total CAPS-5 score after 12 weeks of 
treatment. 
• Proportion of participants with Loss of Diagnosis, defined as Response AND 
no longer meeting DSM-5 symptom criteria in any one or more of the four 
clusters (B, C, D, E) after 12 weeks of treatment. 
• Proportion of participants in Remission, defined as Loss of Diagnosis AND 
Total CAPS-5 score ≤ 10 after 12 weeks of treatment. 
• Proportion of participants achieving sustained Remission, defined as Loss of 
Diagnosis AND Total CAPS-5 score ≤ 10 after both 8 weeks AND 12 weeks 
of treatment.  


 
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• Proportion of participants with a ≥ 50% improvement from baseline in Total 
CAPS-5 score after 12 weeks of treatment. 
• Change from baseline in Beck Depression Inventory–II (BDI-II) score after 12 
weeks of treatment. 
• Change from baseline in CAPS-5 Reckless or Self-Destructive Behavior (item 
E-2) score after 12 weeks of treatment.  
2.2.2 Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include: 
• Change from baseline in the CAPS-5 item for depersonalization (CAPS-5 
item 29) after 12 weeks of treatment 
• Change from baseline in the CAPS-5 item for derealization (CAPS-5 item 30) 
after 12 weeks of treatment. 
2.2.3 Safety Endpoints 
Safety will be assessed by: 
• Adverse events (AE) and serious AEs (SAEs) throughout the entire duration 
of the study, including detailed assessment of AEs involving the oral cavity. 
• Changes from baseline in clinical laboratory test results. 
• Changes from baseline in vital signs and weight. 
• Change from baseline in BDI-II. 
• Changes from baseline in suicidal ideation or behavior as reported on the 
Columbia Suicide Severity Rating Scale (C-SSRS). 
• Changes from baseline in participant-rated Changes in Sexual Functioning 
Questionnaire Short-Form (CSFQ-14). 
• Changes from baseline in participant-rated morning sedation as assessed by 
the Morning Treatment-Related Sedation Score (MTRSS). 
 
 
 


 
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3. OVERALL STUDY DESIGN AND PLAN 
This is a Phase 3, 12-week, randomized, multicenter, double-blind, placebo-controlled, 
fixed dose study that will investigate the efficacy and safety of TNX-102 SL 5.6 mg 
taken daily at bedtime for the management of military-related PTSD.  This study is to be 
conducted at approximately 45 investigational sites in the United States. 
The total duration of this study over 6 visits will be approximately 13-17 weeks, with 12 
weeks of treatment duration and a variable length of screening.  This study will consist of 
a Screening visit (Visit 1, Days −35 to −7), Randomization visit (Visit 2, Day 0), 
telephone visit (Visit 3, Week 2) and three monthly in-clinic visits (Visits 4, 5 and 6 at 
Weeks 4, 8, and 12). 
Eligible participants who provide written informed consent to participate will have study 
assessments performed at Screening, including counseling regarding any required 
washout and instructions to refrain from use of excluded medications throughout the 
study. 
The length of the pre-randomization screening period is variable (7 to 35 days) in order to 
accomplish wash-out of previous medications, where appropriate, and allow for return of 
clinical laboratory results necessary to confirm eligibility.  At Visit 2, participants will 
return to the site for additional baseline assessments and randomization (Day 0), when, if 
they meet all study randomization criteria, they will be randomly assigned in a 1:1 ratio 
to receive placebo or TNX-102 SL 5.6 mg.  A dynamic randomization procedure will be 
employed at Visit 2 to minimize trial-wide imbalances between the treatment groups for 
site, sex, current tobacco/nicotine use (yes/no) and presence (yes/no) of current Major 
Depressive Episode (MDE) based on the Mini International Neuropsychiatric Interview, 
Version 7.0.2 (MINI 7.0.2) conducted at Visit 1. 
Participants will take the study drug sublingually daily at bedtime, starting on the day that 
they are randomized and continuing for 12 weeks.  Participants will return to the study 
center for safety and efficacy assessments at Weeks 4, 8, and 12 (or early termination [ 
ET]). 
 
3.1 Selection of Study Population 
For a complete list of inclusion and exclusion criteria please refer to the initial protocol 
issued 06 October 2016, Amendment 1, dated 03 February 2017, Amendment 2, dated 28 
March 2017 and Amendment 3, dated 18 May 2018. 
3.2 Method of Treatment Assignment and Randomization 
Once all pre-randomization assessments have been completed, only those participants 
who meet all of the following randomization criteria will be eligible to continue: 
1. Participant continues to meet all inclusion and exclusion criteria, including urine 
and blood test results, and 
2. Visit 2 total CAPS-5 score ≥ 33 (“Symptom Severity” version using 1-week 
recall), and 


 
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3. At Visit 2, participant is not severely depressed (based on the investigator’s 
judgment and Visit 2 C-SSRS, CAPS-5, and BDI-II, and considering the pre-
randomization collaborative review by the investigator and medical monitor(s) of 
the participant’s Visit 1 psychiatric history, presenting symptomatology, MINI 
7.0.2, C-SSRS, CAPS-5, and BDI-II assessments).  
4. No active suicidal intent or plan, based on Investigator’s judgment, and Visit 2 C-
SSRS responses (e.g., no C-SSRS Type 4-5 ideation or suicidal behavior since 
Visit 1). 
If the participant meets all study randomization criteria, they will be randomly assigned 
in a 1:1 ratio to receive placebo or TNX-102 SL 5.6 mg for 12 weeks. A dynamic 
randomization procedure will be employed at Visit 2 to minimize trial-wide imbalances 
between the treatment groups for site, sex, current tobacco/nicotine use (yes/no) and 
presence (yes/no) of current MDE based on the MINI conducted at Visit 1. 
 
Treatment A:  2 x TNX-102 SL 2.8 mg tablets (“TNX-102 SL”) to be taken sublingually 
once daily at bedtime. 
Treatment B:  2 x placebo tablets (“placebo”) to be taken sublingually once daily at 
bedtime. 
3.3 Treatment Blinding 
This is a double-blind study.  Unless otherwise specified, all study personnel are to 
remain blinded to study drug.  Treatment assignments will not be revealed until all 
participants have completed the study and the database has been finalized and closed. 
Completion of study may occur due to early stop based on interim analysis results (either 
for futility or efficacy); initial results may be released at that time, followed by a full final 
analysis for the clinical study report. 
 
If AEs occur that are considered to be intolerable, the investigator must decide whether it 
is necessary for the participant to discontinue study drug; however, the investigator 
should not be unblinded unless it is imperative for the participant’s overall safety to 
determine whether the participant received active study drug (e.g., in the event of 
overdose of investigational product).   
 
 
3.4 Minimization of Missing Data / Dropout rate 
It is important to avoid missing data from clinical trials.  The following strategies are 
designed to minimize drop-outs and missing data in this study: 
• Providing participants with greater background on the nature of placebo-
controlled clinical trials and explaining that completing this study, regardless 
of the participant’s level of treatment response, is essential to understanding 
whether TNX-102 SL may be helpful to others in the treatment of PTSD.  
Sites will explain that the study is not designed to benefit the individual 


 
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participant but, rather, can only provide useful information for future 
therapeutics. 
• Minimizing the burden on participants, with visits scheduled generally every 4 
weeks (with reasonable visit window flexibility).  Clinical site personnel will 
also receive guidance regarding the special considerations necessary when 
dealing with participants with military PTSD. 
• Training of site personnel on the importance of minimizing missing data. 
• Providing payment for participants’ time and effort at clinic visits, based on 
the duration of assessments and as approved by the Institutional Review 
Board.  Reimbursement for travel expenses to and from the clinic sites may 
also be provided to further minimize the financial burden of participating in 
the study. 
• Utilizing repeated assessments of outcome measures and analytical 
approaches that most appropriately compensate for missing data. 
• Offering open-label continuation trial(s) for those successfully completing the 
double-blinded study and for randomized participants who have not yet 
completed the study if the study is stopped early for success. 
 
 


 
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4. ANALYSIS AND REPORTING 
4.1 Interim Analysis 
An interim analysis will be performed by a statistical group independent of both the 
sponsor and contract research organization (CRO) performing the final analysis when 
approximately 50% of the initially planned enrollment is evaluable for efficacy 
assessments.  An IDMC will review the data and recommend to the Sponsor to increase 
the sample size by a fixed amount, keep the current sample size and continue, stop the 
study early for success, or stop the study early for futility.   The ISAP, the IDMC charter 
and the Adaptive Study Simulation Report are being submitted together with this version 
of the SAP to the FDA. 
The interim analysis will be conducted approximately 12 weeks after randomization of 
approximately 275 participants, i.e. when approximately 50% of the initially planned 
participant enrollment (550) is evaluable for efficacy assessments. These approximately 
275 participants of the interim analysis will define the Early Stop Efficacy Population 
(see Section 6). 
In case the study is stopped early for success, eligible participants who are not included in 
the early stop efficacy population will be immediately transitioned to an open label 
extension safety study.  
In case the study is stopped early for futility, participants will be managed according to a 
study termination plan. 
In the case of an early stop for futility or efficacy, initial results may be released prior to 
full database lock; however, CSR results will be based on the final analysis described 
below. 
4.2 Final Analysis 
All final, planned analyses will be performed after the last participant has completed all 
study assessments, all relevant study data have been processed and integrated into the 
analysis database, and the database has been locked.  As described above, in the event of 
the interim analysis triggering an early stop for success, only those participants who are 
part of the early stop efficacy population will be analyzed, and eligible participants who 
are not included in the early stop efficacy population will be immediately transitioned to 
an open label extension safety study.  Efficacy assessment will not be done prior to 
transition to TNX-CY-P306.  
Any post-hoc, exploratory analyses completed to support planned study analysis, which 
were not identified in this SAP, will be documented and reported in appendices to the 
CSR.  Any results from these unplanned analyses (post-hoc) will also be clearly 
identified in the text of the CSR. 
 
 




 
Protocol: TNX-CY-P301                                                                                 Page 18 of 43 
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6. ANALYSIS POPULATIONS 
The following analysis populations are planned for this study:  
• Safety Population (SAFETY): All participants who receive at least 1 dose of 
study drug. Participants who are issued study drug, but return 100% of it (i.e., 
none consumed) will be excluded from the safety population; likewise 
participants that have no follow up following receipt of study drug to indicate 
they took drug are excluded.  All safety analyses and demographic/baseline 
characterization will be performed using this population, analyzed as treated; 
participants will be summarized under TNX-102 SL 5.6 mg if they were issued it 
at any visit (including participants that are rolled over to open-label TNX-102 SL 
5.6 mg in the case of an early stop recommended by the IDMC during the planned 
interim analysis).  
• Modified Intention-to-Treat Population (mITT): All randomized participants 
who have at least a baseline and one post-baseline CAPS-5 assessment.  This is 
the primary population for efficacy analyses and participants will be analyzed 
based on their randomized treatment.   
•  Early Stop Safety Population (SAFETY): This population is identical to the 
safety population but is limited to only the participants that are part of the interim 
analysis, (i.e. participants that are ongoing at the time of early stop are excluded).  
In the case of an early stop, safety results will be analyzed on both safety 
populations.  Should the study continue to full enrollment (or full enrollment on 
an increased sample size), this population will not be utilized. 
• Early Stop Efficacy Population (mITT): This population will be limited to 
those participants who are part of the interim analysis, i.e., among the 
approximately 275 patients defined as the population upon which the predefined 
interim analysis efficacy assessments will be conducted.  Only those participants 
who have a baseline and at least one post-baseline CAPS-5 assessment will be 
evaluated for purposes of the interim analysis.  Participants will be analyzed 
based on their randomized treatment.  The dataset for this population will be 
defined by the completion or early termination of the last participant among this 
cohort.   
 
 
 


 
Protocol: TNX-CY-P301                                                                                 Page 19 of 43 
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7. GENERAL ISSUES FOR STATISTICAL ANALYSIS 
7.1 General Statistical Methodology 
Descriptive summaries will be provided where appropriate for each of the primary and 
secondary variables.  In general, tables will summarize data by treatment group and visit.  
Baseline characteristic and safety tables will be completed for the Safety Population 
unless otherwise specified.  Efficacy tables will be presented for the mITT Population.  
Continuous, quantitative, variable summaries will include the number of participants (N) 
with non-missing values, mean, standard deviation (SD), median, minimum, and 
maximum.  
Categorical, qualitative, variable summaries will include the frequency and percentage of 
participants who are in the particular category.  In general, the denominator for the 
percentage calculation will be based upon the total number of participants in the study 
population for the treatment group unless otherwise specified.  
Baseline values are defined as the last non-missing measurement prior to the first dose of 
study drug.  Change from baseline will be defined as the post-baseline visit value minus 
the baseline value.   
ET participants will only be followed if required to monitor an on-going adverse event or 
other condition. 
Participants are not supposed to change study sites; however, should this be necessary to 
allow a participant to continue in the study, participants will be analyzed under the site 
where they were initially enrolled. 
Study day after first dose is defined as assessment date – first dose date +1.  Dates prior 
to first dose are defined as assessment date – first dose date.  Note that the protocol refers 
to “Day 0”; for the purposes of the datasets and analyses, this would appear as day 1. 
All analyses will be performed using Statistical Analysis System (SAS®) Software 
version 9.3 or later.  
Alpha levels are discussed in Section 7.1.1.2 below; unless otherwise noted, 95% 
confidence intervals will be presented for statistical tests. 
Presence of current tobacco/nicotine use and MDE is recorded first in the Interactive 
Web Response System (IWRS) during screening for purposes of randomization 
stratification and, after randomization, transcribed into the electronic data capture (EDC) 
system (as part of substance use history and the results for the MINI).  The source for 
tobacco/nicotine use MDE in all analyses and statistical models will be the EDC data and 
not the IWRS. 
7.1.1 Adjustments for Multiplicity and Other Alpha Control 
7.1.1.1 Multiplicity 
To adjust for multiplicity and to control for overall type I error, a fixed sequence 
procedure will be applied to key secondary efficacy endpoints.  If the primary analysis 
produces a result that is statistically significant at a given level, the key secondary 




 
Protocol: TNX-CY-P301                                                                                 Page 21 of 43 
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7.2.1 Primary Efficacy 
7.2.2 Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) 
The primary efficacy endpoint is the change from baseline in total CAPS-5 score at Week 
12 (Visit 6).  
 
The CAPS-5 is an updated and validated version of a semi-structured interview that has 
been designed to assess the essential features of PTSD as defined by the DSM-5 
(Weathers et al, 2013).  The CAPS-5 affords the clinician flexibility to inquire about 
symptoms and diagnostic status over different time frames, such as past week, past 
month, and/or worst month for lifetime.  For this study, a “Diagnostic” version of the 
CAPS-5 (past month recall) will be utilized at the Screening visit to confirm the diagnosis 
of PTSD and determine eligibility. A “Symptom Severity” version of the CAPS-5 (past 
week recall) will be completed by the clinician at all other time points (Baseline [Visit 2] 
and after 4, 8, and 12 weeks of treatment [Visits 4, 5, and 6]).  
 
The CAPS-5 interview contains the following components 
• Life Events Checklist for DSM-5 (LEC-5): Completed by the participant at the 
Screening Visit (Visit 1 only) 
• Criterion A – Assessment Form (CA-AF):  this semi-structured interview is 
based on the Criterion A discussion included in the CAPS-5, but modified (by 
Dr. Frank Weathers, CAPS-5 lead author) specifically for this study to ensure 
sufficient review of the traumas outlined on the participant-completed LEC-5 
and to capture clear description of the participant’s index/qualifying trauma 
(Visit 1 only) 
• PTSD symptoms, onset/duration, distress/impairment, global rating, and 
dissociative symptoms: 
o Criterion B: Items 1-5 (Intrusion symptoms) 
o Criterion C: Items 6-7 (Avoidance symptoms) 
o Criterion D: Items 8-14 (Negative alterations in cognitions & mood) 
o Criterion E: Items 15-20 (Arousal and reactivity symptoms) 
o Criterion F: Items 21-22 (Onset and duration of symptoms) 
o Criterion G: Items 23-25 (Distress and impairment due to PTSD) 
o Global ratings: Items 26-27 (Validity, severity) 
o Dissociative symptoms: Items 29 (Depersonalization) and 30 
(Derealization) 
 
In addition to the total symptom score (obtained from the sum of Criteria B-E), the 
CAPS-5 affords the opportunity to examine clusters of symptoms, including Criterion B 
(intrusion symptoms), Criterion C (persistent avoidance), Criterion D (negative 
cognitions and mood), and Criterion E (arousal and reactivity), all of which will be 
secondary efficacy endpoints.  
 
In the case of CAPS-5 items that are not resolvable at the site level (via query, review of 
source), the following conventions will be employed for handling of missing CAPS-5 


 
Protocol: TNX-CY-P301                                                                                 Page 22 of 43 
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items: 
• For ≤ 2 missing item scores in Criterion B, D, or E, the average of the other 
items within the criterion will be used for the missing item;  
• For < 2 missing items scores in Criterion C, which only has 2 items, the value of 
the non-missing items will be used for the missing item;  
• For > 2 missing items in Criterion B, D, or E, or > 1 missing item in the 
Criterion C, the total CAPS-5 score will be considered missing overall. 
7.2.3 Key Secondary Efficacy Assessments 
7.2.3.1 Clinician Global Impression of Improvement (CGI-I) 
The CGI-I will be completed by an Investigator to evaluate the participant’s status since 
initiation of treatment.  The CGI-I, status since initiation of treatment, is the first key 
secondary efficacy endpoint in this study.  The CGI-I should be completed toward the 
end of each in-clinic post-Baseline study visit once all other assessments are available for 
the investigator’s review. Once the participant has been randomized, an Investigator 
completes the CGI-I assessment after 4, 8, and 12 weeks of treatment in order to assess 
the overall change in the participant’s status and answer the following question:  
Since the initiation of treatment at Visit 2, the participant is:  
1 = Very much improved  
2 = Much improved  
3 = Minimally improved  
4 = No change  
5 = Minimally worse  
6 = Much worse  
7 = Very much worse 
The key secondary analysis of CGI will treat it as a continuous variable (scored 1-7 as 
above).   There will be an additional outcome presented where a responder on the CGI-I 
is defined a participant who is scored as ‘Very much improved’ or ‘Much improved’ and 
compared between the study arms. 
 
7.2.3.2 Sheehan Disability Scale (SDS) 
The SDS scale is a self-report questionnaire that was designed to assess the participant’s 
view of the degree to which symptoms have disrupted work/school, social life/leisure 
activities, and family life/home responsibilities during the previous two weeks (Sheehan 
& Sheehan, 2008). In addition, the SDS asks the participant to provide the number of 
days of work/school lost as well as unproductive days in the past two weeks.  The SDS 
scale will be completed by the participant at Baseline and after 4, 8, and 12 weeks of 
treatment (Visits 4, 5, and 6, respectively). A total score will be calculated summing the 
three individual 11-point (0-10) scales.  For participants that do not respond to the 
work/school disruption because the participant checked the box indicating he/she has not 
worked or attended school for reasons unrelated to the disorder (PTSD), the total score 
will sum the other two domain questions and multiply by 1.5 (rounding up to the nearest 
whole number) to maintain the scale of 0-30 for the total score.  Participants with missing 


 
Protocol: TNX-CY-P301                                                                                 Page 23 of 43 
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values on the other items will be missing for the total. 
7.2.4 Other Efficacy Outcomes 
7.2.4.1 PROMIS Sleep Disturbance Instrument  
 
PROMIS refers to the Patient-Reported Outcome Measurement Information System 
(www.nihpromis.org), a National Institutes of Health (NIH)-funded initiative to develop 
instruments to be used across chronic conditions.  
The PROMIS sleep disturbance scale (short form 8a) will be assessed at Baseline and 
after 4, 8, and 12 weeks of treatment (Visits 4, 5, and 6, respectively). 
The sleep disturbance scale will be calculated summing the individual item scores of the 
8 items.   These summed scores will be transformed to T-scores using the published 
conversions (see Section 14.2). 
7.2.4.2 Patient Global Impression of Change (PGIC) 
The PGIC is a validated, self-report instrument to gauge the participant’s assessment of 
change in condition.  This form will be completed by the participant after 4, 8, and 12 
weeks of treatment (Visits 4, 5, and 6, respectively).  The participant will answer a single 
question: 
  
Since the initiation of study medication, my PTSD symptoms are:  
1 = Very much improved  
2 = Much improved  
3 = Minimally improved  
4 = No change  
5 = Minimally worse  
6 = Much worse  
7 = Very much worse  
A responder on the PGIC is a participant who scores himself as ‘Very much improved’ or 
‘Much improved.’ 
7.2.4.3 BDI-II 
The Beck Depression Inventory (BDI-II) is a 21-item measure of the severity of current 
depressive symptoms, extensively validated for use in both medical and mental health 
populations.  While this instrument does not provide a psychiatric diagnosis of depression 
and has considerable overlap with PTSD associated symptoms, it does provide a 
continuous scale for measuring changes in the severity of symptomatology.  The BDI-II 
will be completed by the participant at all visits. 
7.2.4.4 CAPS-5 Additional Endpoint Definitions 
7.2.4.4.1 Response 
Response is defined as ≥ 10-point improvement from baseline in CAPS-5 total score. 
7.2.4.4.2 Loss of Diagnosis 


 
Protocol: TNX-CY-P301                                                                                 Page 24 of 43 
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Loss of Diagnosis at any time point is defined as Response AND no longer meeting 
DSM-5 symptom criteria required for diagnosis on the CAPS-5 in any one or more of the 
four clusters (B, C, D, E).  
7.2.4.4.3 Sustained Remission 
Remission at any time point is defined as a Loss of Diagnosis and a CAPS-5 total score 
of ≤ 10. Remission that is sustained is defined by meeting remission criteria after both 8 
AND 12 weeks of treatment.  
A CAPS-5 total score of ≤ 10 was selected for remission based on Frank Weathers 
(National Center for PTSD) communication that empirical data suggested the CAPS-5 
score range from 0 to 10 was “asymptomatic/few symptoms”.  In large multicenter 
pharmacotherapy trials of PTSD that utilized the prior 17-item CAPS for DSM-IV, 
remission was defined as achieving a score of < 20 (Krystal et al, 2011) or ≤ 20 
(Davidson et al, 2006). Direct mathematical extrapolation of a score of 20 on prior CAPS 
version, considering the different scaling for intensity/frequency (0-4 on CAPS-5; 0-8 on 
CAPS for DSM-IV), would be ((remission score of 20/17-items CAPS for DSM-IV)/2 
(scaling))*20-items CAPS-5) = 11.8 or about 12.  Although <12 or ≤12 were considered 
as more comparable with these definitions from studies using the prior version of CAPS, 
the definition of ≤ 10 was ultimately chosen as the more stringent approach. 
 
7.3 Safety Assessments 
Safety will be assessed by: 
• AE and SAEs throughout the entire duration of the study, including detailed 
assessment of AEs involving the oral cavity. 
• Changes from baseline in clinical laboratory test results. 
• Changes from baseline in vital signs and weight. 
• Change from baseline in BDI-II (see Section 7.2.4). 
• Changes from baseline indicative of increased suicidal ideation or behavior as 
assessed by the C-SSRS. 
• Changes from baseline in participant-rated CSFQ-14. 
• Changes from baseline in participant-rated morning sedation as assessed by 
the MTRSS. 
7.3.1 Adverse Event and Prior/Concomitant Medication handling conventions 
To handle missing or partial AE and prior/concomitant medication dates, the following 
rules will be applied. 
For partial start dates: 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2. If the month is unknown, then: 


 
Protocol: TNX-CY-P301                                                                                 Page 25 of 43 
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a. If the year matches the year of the first dose date, then impute the month 
and day of the first dose date. 
b. Otherwise, assign “January.” 
3. If the day is unknown, then: 
a. If the month and year match the month and year of the first dose date, then 
impute the day of the first dose date. 
b. Otherwise, assign “01.” 
 
For partial end dates: 
 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2. If the month is unknown, then assign “December.” 
3. If the day is unknown, then assign the last day of the month. 
 
Adverse events are categorized as either pre-treatment adverse events or treatment-
emergent adverse events based on the response to the CRF question “Did the AE start 
prior to the first dose?” 
After implementing the rules above, to determine whether medications with missing start 
or stop dates are prior or concomitant medications, the following strategy will be used: 
 
1. If the start date and stop date are both missing, then the most conservative 
approach is taken and the medication is considered to be a concomitant 
medication. 
2. If the start date is missing but the stop date is not missing and is after the day of 
first study dose administration, then the most conservative approach is taken and 
the medication is considered to be concomitant. 
3. If the start date is missing but the stop date is not missing and is on or before the 
day of first study dose and after the date of signed informed consent, then the 
medication is considered to be a prior medication. 
4. If the start date is not missing but the stop date is missing, then the most 
conservative approach is taken and medication is considered to be concomitant. 
The missing severity of an AE will be imputed to “severe”; the missing relationship to 
study drug of an AE will be imputed to “related”.  
 


 
Protocol: TNX-CY-P301                                                                                 Page 26 of 43 
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8. STUDY PARTICIPANTS AND DEMOGRAPHICS 
8.1 Disposition of Participants and Withdrawals 
The numbers and percentage of participants randomized, completing the study, and 
withdrawing from the study, along with reasons for withdrawal, will be tabulated overall 
and by treatment group.  The number and percentage of participants in each analysis 
population will be reported.  This summary will be based on all participants who have 
data entered into the database.  
8.2 Protocol Deviations 
Protocol deviations will be checked on complete data for all participants, determined 
during a (blinded) data review meeting before database lock, unblinding, and the final 
analysis. 
Protocol deviations will be summarized by type and by treatment group for the Safety 
population.  Protocol “violations” are not differentiated from deviations; instead, each 
deviation is identified either as “major” or “minor” depending upon its potential impact 
upon the integrity of the study data or the participant’s well-being. 
Individual participants with protocol deviations will be listed. 
8.3 Demographics and Other Baseline Characteristics 
Descriptive summaries of the demographic and other baseline characteristics will be 
completed for all participants in the safety population by treatment groups, unless 
otherwise specified. 
Descriptive summaries of demographic and other baseline conditions will include: 
• Demographics (age, gender, race/ethnicity, height, weight, body mass index 
(BMI), family status, education, presence of current MDE, current nicotine, 
alcohol and THC usage, and employment status).  In addition to the safety 
population, these will also be repeated for all randomized participants and the 
mITT population. 
• Psychiatric history (MINI 7.0.2) 
• Clinician administered scales 
o C-SSRS-Baseline/Screening Version 
o CA-AF 
o CAPS-5 Assessment (Diagnostic version)  
Other assessment’s baseline values will be reported with their respective follow-up 
measures. 
 
Medical History will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 19.0 and summarized by System Organ Class (SOC) and Preferred 
Term using frequency counts by treatment group.   
 
 


 
Protocol: TNX-CY-P301                                                                                 Page 27 of 43 
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9. EFFICACY ANALYSES 
9.1 Primary Efficacy Analysis Approach 
The mean change from baseline in the total CAPS-5 score after 12 weeks of treatment in 
the TNX-102 SL 5.6 mg and placebo arms will be analyzed using a restricted maximum 
likelihood (REML) based repeated measures approach, including multiple imputation for 
missing values and accounting for the two-stage design.  The model will include all 
participants in the mITT population. The dependent variable will be the observed change 
from baseline in total CAPS-5 score at each post-randomization visit.  
9.1.1 Primary Efficacy Analysis 
An adaptive group sequential design will be performed by an independent third party 
statistical group 
 to cover an early efficacy stop, sample size adjustment, or 
futility stop; the final CSR analyses in all cases will be performed by 
 (the primary 
biostatistics vendor). To assure independence of the stage wise test statistics, the first 
stage population is defined as all participants available for efficacy analysis in the interim 
analysis. The second stage population is defined as all participants randomized after the 
interim cut-off and participants randomized prior to the interim cut-off, who were not 
available for efficacy analysis in the interim analysis. 
Participants that drop out or reach Week 12 by the time of the interim cut-off will be 
included into the interim analysis. If the study continues until full planned recruitment, 
participants who were randomized prior to the interim cut-off, but did not drop out or 
reach Week 12 by the time of the interim cut-off, will be included into the second stage 
test statistic. Participants that were randomized after the interim cut-off will be included 
in the calculation of the second stage test statistic. Note that in every case, only 
participants that meet the mITT population criteria will be included. 
If the study is stopped early for efficacy, participants who were randomized prior to the 
interim cut-off but did not drop out or reach Week 12 by the time of the interim cutoff 
will be offered an immediate transition into open label extension safety study (TNX-CY-
P306) and will not be included in the efficacy analyses.  
Data of different stages will be combined using the inverse normal method to test the null 
hypotheses that there is no difference in the change from baseline in CAPS-5 total score 
between TNX-102 SL and placebo treatment groups at Week 12: 
 
𝑍𝑍1  = 𝛷𝛷−1(1 − 𝑝𝑝1) 
𝑎𝑎𝑎𝑎𝑎𝑎 𝑍𝑍2  = 𝑤𝑤1𝑍𝑍1 + 𝑤𝑤2𝛷𝛷−1(1 − 𝑝𝑝2)  
 
Where: 
Z1= the Z statistic for the first stage 
Z2= the combination test statistic at the end of the second stage 
wi = the weighting applied for each associated Z statistic 




 
Protocol: TNX-CY-P301                                                                                 Page 29 of 43 
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likewise ongoing subjects will not be included in final efficacy analyses in the case of a 
futility stop. 
In addition, the least squares means and 95% confidence intervals (CIs) will be calculated 
for the treatment difference between TNX-102 SL and placebo at each time point. 
9.1.2 Sensitivity and Supporting Analyses 
The primary analysis will be followed by two sensitivity analyses to investigate the 
impact of missing data on the treatment estimates.  Additionally, a MAR mixed model 
will be reported for reference. 
9.1.2.1 ‘Other’ Dropouts as MNAR 
This sensitivity analysis will be a repeat of the primary efficacy analysis, but including 
participants that have ‘other’ marked as the reason for drop out included with the 
dropouts reasons to be imputed under the MNAR assumption (imputed values based on 
the baseline distribution). 
9.1.2.2 All dropouts as MNAR 
This sensitivity analysis will be a repeat of the primary efficacy analysis, but imputing all 
dropouts under the MNAR assumption with values based on the baseline distribution. 
9.1.2.3 MAR Mixed Model Repeated Measures 
This analysis will be identical to the primary analysis, but will not include the MI stage 
described above. 
9.1.3 Graphical Representations 
The percent of participants reaching varying levels of improvement in CAPS-5 will be 
displayed in several manners.  For each, the percent of participants will be out of all 
participants in the mITT population; thus, missing participants will be considered to have 
no improvement.  All graphs will be produced with separate bars/lines for each treatment. 
First, a continuous responder graph will be produced with percent improvement to Week 
12 on the X-axis and the percent of participants achieving that level of improvement on 
the Y-axis.  The X-axis will start at 0, so the Y intercept represents participants with any 
improvement; because the X-axis starts at zero and percentages are reported out of the 
mITT population, those with worsening/no improvement and those with missing data will 
be grouped together and their frequency represented by the Y intercept. 
Secondly, a similar graph will be produced, but substituting the absolute change from 
baseline for percent improvement, again with X-axis starting at 0, so the Y intercept 
represents subject with any improvement; those with worsening/no improvement and 
those with missing data will be grouped together. 
Additionally, a bar chart will be presented showing the percent of participants in 10-point 
groupings of Week 12 CAPS-5 scores.  Percent of participants with missing data will be 
reported. 


 
Protocol: TNX-CY-P301                                                                                 Page 30 of 43 
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Finally, a bar chart will be presented showing the percent of participants in 10-point 
groupings of Week 12 change from baseline CAPS-5 scores.  Those with worsening/no 
improvement and those with missing data will be presented as separate groups and the 
percent reported. 
 
9.2 Secondary Efficacy Analysis 
9.2.1 Continuous outcomes 
The analyses of continuous secondary endpoints will be analyzed using an MMRM 
model identical to the primary endpoint, however, there will be no multiple imputation 
applied.   These endpoints will include: 
• CGI-I score. 
• Change from baseline in SDS total.  
• Change from baseline in participants’ quality of sleep using the PROMIS 
Sleep Disturbance scale.  
• Change from baseline in the disruption of work/school activities assessed 
using the SDS.  
• Change from baseline in disruption of social life/ leisure activities assessed 
using the SDS. 
• Change from baseline in the disruption of family life/home responsibilities 
assessed using the SDS. 
• Change from baseline in CAPS-5 Arousal and Reactivity (Criterion E).  
• Change from baseline in CAPS-5 Intrusion symptoms (Criterion B).  
• Change from baseline in CAPS-5 Negative Cognition and Mood (Criterion 
D).  
• Change from baseline in CAPS-5 Persistent Avoidance (Criterion C).  
• Change from baseline in CAPS-5 Sleep Disturbance (item E-6). 
• Change from baseline in CAPS-5 Exaggerated Startle (item E-4). 
• Change from baseline in CAPS-5 Reckless or Self-Destructive Behavior (item 
E-2). 
• Change from baseline in CAPS-5 Depersonalization (item 29). 
• Change from baseline in CAPS-5 Derealization (item 30). 
• PGIC score.  
• Change from baseline in BDI-II score. 
The model will be changed to include the corresponding baseline value of the secondary 
endpoints instead of baseline CAPS-5. Randomized participants who have a baseline and 
at least one post-baseline assessment for the endpoint being analyzed will be included in 
the model.  To estimate the difference between the treatment arms in CGI-I and PGIC 
scores (which do not have baseline assessments), the same method will be used, however, 
with the observed baseline response and associated interactions removed from the list of 
covariates. All visits will be included in the analysis. P-values from these comparisons 
will be considered nominal (conclusions from the sequential testing algorithm will be 


 
Protocol: TNX-CY-P301                                                                                 Page 31 of 43 
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reported separately). 
For each outcome, descriptive statistics (mean, SD, median, minimum and maximum) 
will be reported as well as LS means, standard error (SE) and p-values comparing the 
treatment and placebo arms at each visit.  The time point of primary interest for all the 
above outcomes will be 12 weeks.  In addition, for the SDS, the frequency of participants 
not working or attending school due to reasons unrelated to PTSD will be reported 
overall and within each visit. 
 
9.2.2 Categorical outcomes 
Binary data over time will be analyzed using a Cochran Mantel Haenszel (CMH) test 
stratified by presence of current major depressive episode.  Examples include the CGI-I 
and the PGIC, in which responders are defined as those who score ‘2’ (much improved) 
or ‘1’ (very much improved) on these 7-point scales. Participants with missing data will 
be analyzed as though they are non-responders. This will be reported for each visit with 
the primary time point of interest at Week 12 (with remission spanning data at weeks 8 
and 12).  Odds ratios for treatment contrasts along with two-sided 95% CIs will also be 
reported.  Two-sided p-values for the test of no difference between the TNX-102 SL and 
placebo will be provided. 
 
These endpoints will include: 
• Proportion of participants with a PGIC score of “much improved” or “very 
much improved”.  
• Proportion of participants with a CGI-I score of “much improved” or “very 
much improved”. 
• Proportion of participants with a Total CAPS-5 score of 0 –10 
(asymptomatic/few symptoms).  
• Proportion of participants with a Total CAPS-5 score of 0-22 (asymptomatic 
or mild PTSD/subthreshold). 
• Proportion of participants with Response, defined as a ≥ 10-point 
improvement from baseline in Total CAPS-5 score. 
• Proportion of participants with Loss of Diagnosis, defined as Response AND 
no longer meeting DSM-5 symptom criteria in any one or more of the four 
clusters (B, C, D, E). 
• Proportion of participants in Remission, defined as Loss of Diagnosis AND 
Total CAPS-5 score ≤ 10.   
• Proportion of participants achieving sustained Remission, defined as Loss of 
Diagnosis AND Total CAPS-5 score ≤ 10 after both 8 weeks AND 12 weeks 
of treatment.  
• Proportion of participants with a ≥50% improvement from baseline in Total 
CAPS-5 score. 
 
 


 
Protocol: TNX-CY-P301                                                                                 Page 32 of 43 
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10. SAFETY AND TOLERABILITY ANALYSIS 
The safety analysis will be run on the Safety population.  The analysis of safety 
assessments in this study will include summaries of the following safety and tolerability 
data collected for each participant: 
• Adverse Events 
• Clinical Laboratory Investigations  
• C-SSRS 
• Vital Signs  
• Visual Examinations of Oral Cavity 
• Electrocardiogram (ECG) Parameters (Obtained at Screening only) 
• Assessment of Morning Sedation (via MTRSS) 
• Changes from baseline in participant-rated CSFQ-14 
• BDI-II 
Summaries of continuous parameters will include raw values and change from baseline, 
as appropriate. Listings of safety data will also be presented. 
10.1 Adverse Events 
All AEs, treatment-emergent adverse events (TEAEs), and SAEs will be coded using 
MedDRA, version 19.0. 
TEAEs are defined as either new onset AEs with an onset at the time of or following the 
start of treatment through ten days after the last dose of study medication, or a recurrence 
of an AE (or medical history) present prior to randomization but increasing in severity, 
frequency or relationship at the time of or following the start of treatment  
An AE summary table will be presented for the following: 
• TEAEs by severity 
• TEAEs leading to study drug discontinuation  
• TEAEs by relationship 
• SAEs 
Summaries of incidence rates (frequencies and percentages) of individual AEs by 
MedDRA SOC and preferred term will be prepared.  Such summaries will be displayed 
for all TEAEs, TEAEs by maximum severity, and TEAEs by strongest relationship to 
study drug. 
Each participant will be counted only once within each summation level (SOC; preferred 
term). If a participant experiences more than one TEAE within each summation level 
only, the TEAE with the strongest relationship or the maximum severity, as appropriate, 
will be included in the summaries of relationship and severity. 
Adverse events of special interest pertaining to abuse potential (as defined in the January 
2017 Assessment of Abuse Potential for Drugs – Guidance for Industry) will be analyzed 
separately by treatment group, SOC and preferred term, and displayed in tabular format.  


 
Protocol: TNX-CY-P301                                                                                 Page 33 of 43 
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In the AE data listings, all AEs will be displayed.  AEs that are treatment-emergent will 
be flagged. 
10.1.1 Adverse Events Leading to Discontinuation of Study Drug  
A summary of incidence rates (frequencies and percentages) of TEAEs leading to 
discontinuation of study drug by treatment group, SOC, and preferred term will be 
prepared for the Safety population.  
A data listing of AEs leading to discontinuation of study drug will also be provided, 
displaying details of the event(s) captured on the CRF. 
10.1.2 Serious Adverse Events 
A summary of incidence rates (frequencies and percentages) of SAEs by treatment group, 
SOC, and preferred term will be prepared for the Safety population.  A data listing of 
SAEs will also be provided, displaying details of the event(s) captured on the CRF. 
10.1.3 Deaths 
A listing of deaths will also be provided for the Safety Population. 
10.2 Clinical Laboratory Evaluations 
Laboratory data include analyses for Chemistry and Hematology and will be summarized 
by treatment and visit for the Safety Population.  Descriptive summaries of actual values 
and changes from baseline will be presented by study visit and each treatment group. 
95% confidence intervals will be presented for change from baseline for each visit and 
last on-treatment assessment.  ET data will be analyzed with the closest visit that does not 
have a valid assessment value. 
Laboratory values will be displayed in the data listings and those that are outside the 
normal range (“H” or “L”) will be flagged, along with corresponding normal ranges.  
Values pre-defined as potentially clinically significant (“HH” or “LL”) will also be 
flagged.  For each laboratory analysis, shifts in assessments of abnormality from baseline 
to each scheduled time point will be presented in shift tables.   
A by-participant listing of all clinical laboratory data will also be provided. 
10.3 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is an instrument that measures suicidal ideation and behavior.  Items 
measuring suicidal ideation and suicidal behavior are displayed in the table below.  
Frequency counts of yes/no responses to items below and whether any suicidal ideation 
or behavior is present will be summarized as described below.  
The overall number of participants with lifetime and/or recent (past 6 months) suicidal 
ideation (by item, e.g., Ideation Types 1-5), and lifetime and/or recent (past 12 months) 
suicidal behavior (by item; e.g., Preparatory Act, Aborted Attempt, Interrupted Attempt, 
Actual Attempt and Completed Suicide), or non-suicidal self-injurious behavior at the 
screening and baseline visit will be summarized by visit and treatment group.  
Additionally, the overall number of participants with any suicidal ideation or behavior 
(by type and in total) or self-injurious behavior while on-treatment will be provided by 


 
Protocol: TNX-CY-P301                                                                                 Page 34 of 43 
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treatment group.  For ideation, participants will only be counted once at each visit and/or 
time frame at the worst case response for ideation type (1-5), where 1 is the least severe 
and 5 is the most severe type of ideation.      
Category 
Items 
A) Suicidal 
Ideation 
(1) Type 1:  Wish to be dead 
(2) Type 2:  Non-specific active suicidal thoughts 
(3) Type 3:  Active suicidal ideation with any methods (not plan) 
without intent to act 
(4) Type 4:  Active suicidal ideation with any some intent to act, 
without specific plan 
(5) Type 5:  Active suicidal ideation with specific plan and intent 
 
B) Suicidal 
Behavior 
(1) Preparatory acts or behavior 
(2) Aborted attempt 
(3) Interrupted attempt 
(4) Actual attempt 
(5) Completed suicide 
 
Suicidal Behavior present (composite of items 1-5) 
Non-Suicidal Self-Injurious Behavior 
 
Suicidal intensity of ideation will be calculated by tallying up the five intensity items to 
create a total score ranging 0-25.  If a participant does not have any suicidal ideation, a 
score of 0 will be given.  Separate tables will be created for the entire Safety Population 
as well as the population comprising only participants exhibiting any suicidal ideation.  
Suicidal intensity of ideation total score will be summarized using descriptive statistics 
by treatment group. 
A data listing of C-SSRS results will include only participants with suicidal ideation, 
suicidal behavior, or self-injurious behavior without suicidal intent.  For participants with 
suicidal ideation, suicidal behavior, or self-injurious behavior without suicidal intent at 
any time, data from all visits are displayed. 
10.4 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values 
and changes from baseline at each assessment time point and last on-treatment 
assessment will be calculated for vital signs including weight, BMI, body temperature, 
pulse rate, systolic blood pressure and diastolic blood pressure. 95% confidence intervals 
will be presented for change from baseline. 
These summaries will be presented by treatment and assessment time for the Safety 
population.  ET data will be analyzed with the closest visit that does not have a valid 
assessment value. 
10.5 Physical Examination and Visual Examination of Oral Cavity 
A full physical examination will be performed at Screening Visit 1 only.  A data listing of 
the physical examination results will be performed.   


 
Protocol: TNX-CY-P301                                                                                 Page 35 of 43 
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A visual examination of the oral cavity will be assessed at Screening, Baseline, and Week 
12.  A visual examination is to be done any time a participant spontaneously reports an 
oral adverse event (aside from AEs known to be sensory-only, such as numbness, tingling 
or bitter taste) to confirm presence or absence of any signs of irritation or other visible 
abnormalities.  A data listing of the visual examination results performed at each 
scheduled visit and at the time of an adverse event will be presented. 
 
10.6 Electrocardiogram (ECG) 
A 12-lead ECG will be performed only at the Screening Visit.  The standard ECG 
parameters including rhythm, heart rate, and intervals for PR, QRS, QT and QTcF 
(Fridericia’s) correction for heart rate will be recorded.  A data listing of ECG results will 
be provided.  
 
10.7 Assessment of Sedation Morning Treatment-Related Sedation Score (MTRSS) 
The MTRSS is designed to assess the participant’s one-week recall of morning sedation 
as assessed at clinic visits. The MTRSS will be assessed at Baseline (Visit 2) and at 
Weeks 4, 8, and 12 (Visits 4, 5, and 6). The participant will complete the following 
questions: 
(A) On most mornings during the past week, I have awakened feeling: 
0. Alert with no grogginess 
1. Mildly groggy 
2. Moderately groggy 
3. Very groggy 
(B) If you reported any grogginess in the last week (responses 1-3), the grogginess lasted: 
1. A few minutes 
2. A short time (less than one hour) 
3. A long time (more than one hour) 
Note: if “Alert with no grogginess is selected in Part A, Part B is not completed, and the 
score for part B is 0 
Results will be summarized with counts and percentages at each visit. 
 
10.8 Assessment of Changes in Sexual Function: Changes in Sexual Functioning 
Questionnaire Short-Form (CSFQ-14) 
The CSFQ-14 (Keller et al. 2006) is validated scale with internal reliability designed to 
allow a participant to self-evaluate his or her sexual behaviors or problems in several 
areas.  The CSFQ-14 will be administered at Baseline (Visit 2) and Week 12/ET (Visit 
6).  It yields a total score, three subscales corresponding to phases of the sexual response 
cycle (i.e. desire, arousal, orgasm), and five subscales corresponding to important 
dimensions of sexual functioning.  It is considered a useful scale for assessing sexual side 
effects of medications.  For all items, higher scores reflect higher sexual functioning.  For 


 
Protocol: TNX-CY-P301                                                                                 Page 36 of 43 
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12 of the 14 items, higher sexual functioning corresponds to greater frequency or 
enjoyment/pleasure (e.g. 1=never to 5 = every day).  For two items (item 10, assessing 
loss of interest after arousal for women and priapism for men, and item 14, assessing 
painful orgasm), higher sexual functioning corresponds to lower frequency (e.g. 1=every 
day to 5=never). Items 10 and 14 are included in the total score but not in any scale score. 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values 
and changes from baseline at each assessment time point will be reported.  
 
 
 


 
Protocol: TNX-CY-P301                                                                                 Page 37 of 43 
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11. MEDICATIONS 
11.1 Concomitant Medication 
All medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) Version September 2016.  Prior and concomitant medications will be 
summarized by treatment group and by the number and percentage of participants taking 
each medication, classified by using WHO-DD Anatomical Therapeutic Chemical Level 
3 and preferred term.  
Prior medications are defined as medications or therapies initiated prior to the start of the 
study drug and terminating prior to the start of study drug.  Hence, these medications or 
therapies will have end dates prior to the first dose date of study drug.  Concomitant 
medications are defined as any medications other than the study drug that a participant 
receives concurrently with the study drug.  These medications will have end dates on or 
after the first dose date of the study drug until ten days after last dose date.   
Prior and Concomitant medications will be summarized.  All medications will be 
presented in a listing.  
Participants’ Lifetime Prior Psychiatric Medications (i.e., discontinued ≥ 60 days prior to 
the Screening visit) will also be summarized by treatment group and by the number and 
percentage of participants taking each medication, classified by using WHO-DD 
Anatomical Therapeutic Chemical Level 3 and preferred term.  
Please refer to Section 7.3 for the conventions used to impute partial start dates and end 
dates of concomitant medications.  
11.2 Exposure and Compliance 
The treatment duration will be calculated as (number of days=last dose date - first dose 
date+1) and summarized.  Participants that are lost to follow up or have a missing last 
dose date will be assigned a last dose date of the day before the last attended clinic visit 
for analysis purposes.    
All pill count shortage (negative pill count) of greater than 4 doses (8 tablets) per 4-week 
assessment period and/or any between-visit compliance <70% will be considered 
protocol deviations, and the reason for the pill count discrepancy will be discussed with 
the participant and documented in the CRF to ensure that any cases of potential abuse or 
misuse are identified.  Participants with more than one significant incidence of negative 
pill count discrepancy during the double-blind phase of the study will be closely 
monitored by the investigator.  
Exposure will be measured using the last date of treatment and first date of treatment.  
Total exposure will be defined as the last date of treatment minus the first date of 
treatment plus one.  The number of participants with total exposure by visit weeks (≤ 4 
weeks (study day 0 to 28), 4 to ≤ 8 (study day 29 to 56), 8 to ≤ 12 (study day 57 to 84) 
and > 12 weeks (study day ≥ 85)) will be presented.  Additionally, exposure days, defined 
as the total number of tablets taken divided by 2 (and rounded up to the nearest whole 
number), will be summarized.   


 
Protocol: TNX-CY-P301                                                                                 Page 38 of 43 
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Compliance will similarly be summarized across all study visits for each treatment arm.  
Study drug compliance as a percentage will be defined as the number of pills taken by the 
participant divided by the total number of pills that the participant was assigned to take 
multiplied by 100.   
For calculating the compliance and exposure days, the following convention will be 
applied:  for periods where drug is issued, but the participant does not return any bottles 
or tablets, or the participant misses the visit entirely, that period will not contribute to the 
compliance or exposure calculation unless the bottles are returned at a later visit. 
Compliance will be summarized with descriptive statistics by treatment arm.  The 
number and percentages of participants within certain categories of compliance e.g. < 
50%, 50% to < 70%, 70% to <= 100%, greater than 100% will be presented. Compliance 
between 70% to 114% will not be considered a protocol deviation.  Tablet counts, 
calculation of compliance overall and by visit, and participant-reported reasons for all 
tablet discrepancies at all visits will be presented in a listing.  
In addition, participants with significant over-usage or otherwise unaccounted-for 
missing tablets resulting in >114% compliance for any visit (e.g., failure to return >8 
tablets per 4 week interval) will be summarized by visit and overall. These listings will 
include both the participant-reported reason for the discrepancy plus the investigator’s 
assessment of potential abuse, misuse or diversion.  Tables will be created for higher 
level abuse-related MedDRA terms.  Clinically significant drug accountability 
discrepancies associated with missing medication, loss of drug, or cases in which the PI 
confirms concern over drug abuse, misuse or diversion, will be examined and discussed 
in the CSR.   
 
12. CHANGES FROM PLANNED ANALYSIS 
Study day as it appears in data listings and the Study Data Tabulation Model (SDTM) 
and Analysis Data Model (ADaM) datasets will differ from the protocol:  The protocol 
describes the day of first dose as “Day 0”; the listings and datasets will conform to the 
standard of first dose day appearing as “Day 1”. 
 


 
Protocol: TNX-CY-P301                                                                                 Page 39 of 43 
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13. REFERENCES 
Adaptive Study Simulation Report for TNX-CY-P301 Final v2.0, 07 May 2018.  
Guidance for Industry Adaptive Design Clinical Trials for Drugs and Biologics, U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research 
(CBER), February 2010. 
IDMC Charter for TNX-CY-P301 Final v3.0, 10 May 2018. 
Interim Statistical Report for TNX-CY-P301 Final v3.0, 16 May 2018.  
January 2017 Assessment of Abuse Potential for Drugs – Guidance for Industry 
Protocol No. TNX-CY-P301 (06 October 2016), Amendment 1, Dated 03 February 2017, 
Amendment 2, Dated 28 March 2017 and Amendment 3, Dated 18 May 2018 
Carpenter, J. R. & Kenward, M. G. (2013), Multiple Imputation and Its Application. 
Chichester, UK: Wiley. 
Davidson J, Rothbaum BO, Tucker P, Asnis G, Benattia I, Musgnung JJ. Venlafaxine 
extended release in posttraumatic stress disorder: a sertraline- and placebo-controlled 
study. J Clin Psychopharmacol. 2006;26(3):259-67. 
Keller A, McGarvey EL, Clayton AH. Reliability and construct validity of the changes in 
sexual functioning questionnaire Short form (CSFQ-14). J of Sex and Marital Ther. 2006; 
32:43-52. 
Krystal JH, Rosenheck RA, Cramer JA, Vessicchio JC, Jones KM, Vertrees JE, Horney 
RA, Huang GD, Stock C; Veterans Affairs Cooperative Study No. 504 Group. 
Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic 
military service-related PTSD: a randomized trial. JAMA. 2011;306(5):493-502. 
Lehmacher, W., Wassmer, G. Adaptive sample size calculations in group sequential 
trials. Biometrics 1999;55: 1286-1290. 
Mallinckrodt C, Roger J, Chuang-Stein C, Molenberghs G, Lane PW, O’Kelly M, Ratitch 
B, Xu L, Gilbert S, Mehrotra DV, Wolfinger R, Thijs H. (2013), Missing Data: Turning 
Guidance Into Action, Statistics in Biopharmaceutical Research, 5:4, 369-382 
Sheehan KH & Sheehan DV. Assessing treatment effects in clinical trials with the Discan 
metric of the Sheehan Disability Scale. Int Clin Psychopharmacol 2008:23:70-83.  
Weathers FW, Blake DD, Schnurr PP, Kaloupek DG, Marx, et al. The Clinician-
Administered PTSD Scale for DSM-5 (CAPS-5). 2013: Instrument available from the 
National Center for PTSD at www.ptsd.va.gov.  
 
 


 
Protocol: TNX-CY-P301                                                                                 Page 40 of 43 
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14. APPENDICES 
14.1 Appendix 1 
The following reporting conventions will be adopted for the presentation of study data.  
These conventions will enhance the review process and help to standardize presentation 
with common notations. 
14.1.1 General Reporting Conventions 
• All tables and data listings will be developed in Landscape Orientation, unless 
presented as part of the text in a clinical study report (CSR). 
• Figures will be presented in Landscape Orientation, unless presented as part of 
the text in a CSR. 
• Legends will be used for all figures with more than one variable or item 
displayed. 
• Figures will be in black and white, unless color figures have been identified as 
useful for discriminating presentation in the figure.  Lines in figures should be 
wide enough to view the line after being photocopied.  
• Specialized text styles, such as bolding, italics, borders, shading, superscripted 
and subscripted text will not be used in tables, figures, and data listings unless 
they add significant value to the table, figure, or data listing.  
• Only standard keyboard characters should be used in tables and data listings. 
Special characters, such as non-printable control characters, printer specific, 
or font specific characters, will not be used on a table, figure, or data listing. 
Hexadecimal character representations are allowed (e.g., µ, α, β). 
• All titles will be centered on a page.  The ICH numbering convention is to be 
used for all tables, listings, and graphs (TLGs). 
• All footnotes will be left justified at the bottom of a page.  Footnotes must be 
present on the page where they are first referenced.  Footnotes should be used 
sparingly and must add value to the TLG.  If more than four footnote lines are 
planned then a cover page may be used to display footnotes. 
• Missing values for both numeric and character variables will be presented as 
blanks in a table or data listing.  A zero (0) may be used if appropriate to 
identify when the frequency of a variable is not observed. 
• All date values will be presented as DDMMMYYYY (e.g., 29AUG2001) 
format.  A four-digit year is preferred for all dates. 
• All observed time values will be presented using a 24-hour clock HH:MM:SS 
format (e.g., 01:35:45 or 11:26).  Seconds should only be reported if they 
were measured as part of the study.  
• Time durations will be reported in mixed HHhr MMm SSs notation (e.g., 5h 
32m, or 27h 52m 31s).  The use of decimal notation to present (display) time 


 
Protocol: TNX-CY-P301                                                                                 Page 41 of 43 
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durations should be avoided (e.g. 0.083h = 5m) unless it is necessary to show 
the computation of time differences in a table, figure, or data listing, in which 
case both notations may be used to display the time duration.  
• All TLGs will have the name of the program, location, programmer, and a 
date stamp on the bottom of each output.  
• All analysis programs developed for a TLG display will be self-contained to 
facilitate transfer of programs to multiple computing environments and 
transfer to a regulatory agency (if requested).  
14.1.2 Population Summary Conventions 
• Population(s) represented on the tables or data listings will be clearly 
identified in the last title of the Table as “<name of population>” and will be 
identical in name to that identified in the protocol or SAP. 
• Consistent terminology will be used to define and identify a population.  
Common nomenclature may include (a) All Participants, (b) ITT, (c) Safety, 
and (d) PP. 
• Sub-population(s) or special population(s) descriptions will provide sufficient 
detail to ensure comprehension of the population (e.g., MITT >60 years of 
age) used for analysis in a table or figure. 
• Population sizes may be presented for each treatment or dosing category as 
totals in the column header as (N=xxxx), where appropriate.  
• Population sizes shown with summary statistics are the samples sizes (n) of 
Participants with non-missing values.  
• All population summaries for categorical variables will include all categories 
that were planned and for which the Participants may have had a response.  
Percentages corresponding to null categories (cells) will be suppressed. 
• All population summaries for continuous variables will include: n, mean, SD, 
minimum, and maximum.  Other summaries (e.g. number missing, median, 
quartiles, 95% confidence intervals, CV or %CV) may be used as appropriate. 
• All percentages are rounded and reported to a single decimal point (xx.x%).  
A percentage of 100% will be reported as 100%.  A percentage of zero will be 
reported as 0. 
• Population summaries that include P values will report the P value to 
three decimal places with a leading zero (0.001).  All P values reported on 
default output from statistical software (i.e., SAS® Software) may be reported 
at the default level of precision. P values <0.001 should be reported as <0.001 
not 0.000. 
 
 


 
Protocol: TNX-CY-P301                                                                                 Page 42 of 43 
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14.2 Appendix 2: PROMIS T-score Conversions 
 
 
 
 
 


 
Protocol: TNX-CY-P301                                                                                 Page 43 of 43 
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14.3 Appendix 3: Seeds for Imputation: 
The following is the list of seeds to be used for any imputations; they will be used in the 
order that they appear in the production dataset programming first for primary analyses, 
then secondaries in the order given in this SAP.  In the instance that a sample size 
increase is needed, the post-interim imputations will use a seed that is 10 greater than the 
one used on the corresponding pre-interim code.   If the list below is insufficient for the 
number of seeds required, the list will repeat with values 1 greater than those given. 
 
9529179445 
4148794564 
6635287595 
3215648962 
5558675309 
4529575352 
3242564245 
8884574838 
5364925865 
5666852284