Clinical trial NCT05686408
Conditions: Depression Depressive Disorder Depressive Symptoms Depressive Disorder, Major Depressive Episode Depression Severe
Sponsor: Tonix Pharmaceuticals, Inc.
Start date: 2023-03-02; Completion date: 2023-09-29
Enrollment: 132 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of TNX-601 ER monotherapy versus placebo in patients with Major Depressive Disorder (MDD).

Detailed description:

Arms: arm 1: 1x TNX-601 ER, 39.4 mg, tablet taken orally once daily for 6 weeks. arm 2: Placebo tablet taken orally once daily for 6 weeks.
Interventions: intervention 1: TNX-601 ER intervention 2: Placebo
Intervention descriptions: intervention 1: Patients will take 1 tablet orally once daily for 6 weeks. intervention 2: Patients will take 1 tablet orally once daily for 6 weeks.

Protocol documents:
Prot_000.pdf: 


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INVESTIGATOR’S AGREEMENT 
I have read the TNX-TI-M201 protocol and agree to conduct the study as outlined.  I also 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-601 ER (tianeptine hemioxalate extended-release tablets) 
Name of Active Ingredient: 
Tianeptine hemioxalate 
Title of Study: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the 
Efficacy, Safety, and Tolerability of TNX-601 ER Monotherapy versus Placebo in Patients with 
Major Depressive Disorder (MDD) 
Study center(s):  Approximately 30 sites in the United States 
Study Population:  Male and female patients aged 18 to 65 years (inclusive) with a diagnosis of 
MDD as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 
criteria, currently suffering from a major depressive episode (MDE). 
Objectives: 
Primary: 
To evaluate the efficacy of TNX-601 ER (tianeptine hemioxalate extended-release tablets) 
monotherapy in the treatment of major depressive disorder (MDD)  
Secondary: 
To evaluate the safety and tolerability of TNX-601 ER (tianeptine hemioxalate extended-release 
tablets) monotherapy in the treatment of MDD 
Methodology: 
This is a 6-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to 
evaluate the efficacy, safety, and tolerability of TNX-601 ER, 39.4 mg monotherapy, on symptoms of 
depression in adult patients with MDD. 
 
There will be a screening and washout period of up to 35 days, a double-blind treatment period 
(during which patients will receive either TNX-601 ER or placebo in a 1:1 randomization ratio) of 
about 42 days, and a posttreatment safety follow-up period of approximately 14 days after 
discontinuation of study drug.  
 
Patients will be consented and screened at Screening (Visit 1) for the study until approximately 300 
patients are randomized. Randomization will be performed in a 1:1 ratio to one of 2 treatment arms 
(daily TNX-601 ER or placebo) after meeting DSM-5 diagnostic criteria for MDD in a current MDE 
as assessed by the Mini International Neuropsychiatric Interview, Version 7.0.2 (MINI 7.0.2) at 
Screening (Visit 1). The TNX-601 ER dose for all eligible patients will be 1 tablet once daily in the 
morning, initiated at Baseline (Visit 2). All patients will return to their respective study site for an off-
drug, Post Study Follow-up (Visit 6) approximately 2 weeks after discontinuation of study drug. 
Overall duration in the study for each patient is expected to be up to 13 weeks. 
Number of patients (planned):  
Approximately 300 patients with MDD will be enrolled. Randomized patients who withdraw will not 
be replaced. 
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Inclusion Criteria: 
1. Female or male aged 18 to 65 years (inclusive).  
2. Have a primary DSM-5 diagnosis of current MDD. 
a) The duration of the current MDE must be at least 12 weeks.  
b) Without psychotic or catatonic features.  
3. Have a Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥28 at Screening (Visit 1), 
≥25 at Baseline (Visit 2), and a ≤25% decrease or increase in MADRS score from Screening 
(Visit 1) to Baseline (Visit 2). 
4. No acute or potentially confounding medical disorders based on medical history, physical and 
brief neurological exam, vital signs, clinical laboratory tests, and 12-lead electrocardiogram 
(ECG) performed at Screening (Visit 1) and Baseline (Visit 2). 
5. If female, is either not of childbearing potential (defined as postmenopausal for at least 1 year or 
surgically sterile [eg, bilateral oophorectomy or hysterectomy]) or will be practicing one of the 
following methods of birth control throughout the study and for 4 weeks following the last dose 
of the study drug (TNX-601 ER or placebo): 
a) Hormonal methods, such as oral, implantable, injectable, or transdermal contraceptives, for a 
minimum of 1 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 jelly 
or cream). 
d) Bilateral tubal ligation. 
e) Partners of vasectomized males in stable relationships; 
f) Females not involved in heterosexual relationships. 
6. Male patients agree to use a reliable method of birth control, as defined above, during the study and 
for at least 4 weeks following the last dose of TNX-601 ER or placebo. 
7. Capable of reading and understanding English and able to provide written informed consent to 
participate. Separate written, signed informed consent will be required if the patient is to 
participate in the optional pharmacogenomic assessment. A decision not to participate in the 
optional pharmacogenomic assessment will not affect the patient’s eligibility for the main study. 
8. Are judged to be reliable and agree to keep all appointments for clinic visits, tests, and 
procedures, including venipuncture, and examinations required by the protocol. 
Exclusion Criteria: 
1. Psychiatric History: 
a) Diagnosis of DSM-5-defined lifetime bipolar disorder (I, II, or unspecified), schizophrenia, 
schizoaffective disorder, MDD with psychotic features, other psychotic disorder, or antisocial 
personality disorder; current (past month) obsessive-compulsive disorder; current (past 
month) posttraumatic stress disorder; current (past 3 months) anorexia nervosa; lifetime 
opioid or lifetime sedative-hypnotic use disorders, as confirmed by the MINI 7.0.2.  
b) Diagnosis of borderline personality disorder that is known, suspected, or as suggested by a 
score of ≥7 on the McLean Screening Instrument for Borderline Personality Disorder (MSI-
BPD).  
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c) Patients with comorbid generalized anxiety disorder (GAD), social anxiety disorder (SAD), 
or panic disorder are excluded only if the GAD, SAD, or panic disorder is considered the 
primary psychiatric diagnosis, rather than MDD. (If MDD is the primary diagnosis, patients 
with comorbid GAD, SAD, and panic disorder are allowed for randomization).  
2. Increased risk of suicide on the basis of 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, or if any of the following results are obtained:  
a) High suicidality based on a MINI 7.0.2 Module B score ≥17 (Screening [Visit 1]); or, 
b) Patient answers YES to either MINI question B10 or B11 (Screening); or, 
c) Patient meets criteria for CURRENT Suicidal Behavior Disorder on the MINI 7.0.2 
(Screening [Visit 1]); or, 
d) A positive response to the Columbia Suicide Severity Rating Scale (C-SSRS) questions for 
Type 4 or Type 5 suicide ideation within 6 months of Screening (Visit 1) or at Baseline (Visit 
2); or, 
e) Any suicidal behavior in the past 12 months as identified by the C-SSRS at Screening (Visit 
1) or between Screening (Visit 1) and Baseline (Visit 2) as identified by the C-SSRS at 
Baseline (Visit 2); or, 
f) A score of >4 on Item 10 of the MADRS at Screening (Visit 1) or Baseline (Visit 2). 
3. Patients with treatment refractory MDD, ie, previously having in their lifetime failed ≥2 
treatments with at least 2 different classes of antidepressants of adequate dose, duration, and 
treatment adherence as assessed by the Investigator at Screening (Visit 1). 
4. Positive urine drug screen results for illicit or abused substances other than cannabis at Screening 
(Visit 1) or Baseline (Visit 2), or history of substance and/or alcohol use disorder during the 
preceding 12 months as evaluated by the MINI 7.0.2 at Screening (Visit 1). 
5. Use of the following concomitant medications:  
a) antidepressants (including St. John’s Wort, S-adenosyl methionine, and/or trazodone used as 
an antidepressant) within 4 weeks of Baseline (Visit 2), except for fluoxetine, which must not 
be within 6 weeks of Baseline (Visit 2);  
b) Monoamine oxidase inhibitors (MAOIs) within 4 weeks of Baseline (Visit 2); 
c) oral atypical antipsychotics used for antidepressant augmentation within 4 weeks of Baseline 
(Visit 2). Patients on antipsychotics for other reasons, or patients taking conventional 
antipsychotics are not eligible;  
d) lithium used for antidepressant augmentation within 4 weeks of Baseline (Visit 2). Patients on 
lithium for other reasons are not eligible; 
e) stimulants, benzodiazepines, or buspirone within 1 week of Baseline (Visit 2);  
f) trazodone used as a hypnotic within 1 week of Baseline (Visit 2);  
g) patients on chronic opioids are not eligible. Opioid use is not allowed during the study 
treatment period;  
h) any use of anticonvulsants other than prophylactic use for migraine. 
6. Have had electroconvulsive treatment, transcranial magnetic stimulation, vagal nerve stimulation, 
or treatment with ketamine or esketamine for MDD. 
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7. Have initiated psychotherapy or have had a change in psychotherapy or other nondrug therapies 
(such as acupuncture or hypnosis) within 12 weeks prior to Screening (Visit 1) , and/or not 
willing to refrain from initiating such treatment during the course of the study. 
8. A body mass index (BMI) of <18.0 or >40.0 kg/m2 
9. The patient has a history of sleep apnea that is severe, uncontrolled, or untreated.  Patients with 
mild obstructive sleep apnea (eg, apnea/hypopnea index 5-15), and/or patients, whose mild to 
moderate sleep apnea is well-controlled with CPAP or oral device, are allowed at the discretion of 
the Investigator. 
10. Have any other clinically significant medical, psychiatric, or social condition prior to 
randomization that, in the opinion of the Investigator, could affect patient safety, preclude 
evaluation of response, interfere with the ability to comply with study procedures, or prohibit 
completion of the study. Examples include hematologic disease or cancer with <5 years remission 
(other than treated carcinoma in situ of the cervix, basal cell carcinoma, or Type 1 squamous cell 
carcinoma of the skin). 
11. Diagnosed with clinically significant and currently relevant cardiac disease (eg, arrhythmia that is 
symptomatic or requires treatment, 2nd- or 3rd-degree AV block, complete right or left bundle 
branch block, heart failure, or recent myocardial infarction [within the past 2 years]) or 
QT corrected for heart rate using Fridericia’s formula (QTcF) >450 msec (male) or >470 msec 
(female) on the ECG at Screening Visit 1). 
12. Evidence of human immunodeficiency virus (HIV) infection based on medical history. 
13. Seizure disorder other than history of childhood febrile seizures. 
14. Hypersensitivity to tianeptine, or any of the excipients in the study drug. 
15. Moderate or severe comorbid traumatic brain injury (TBI) by history. Based on past history and 
Investigator’s judgment, patients with mild TBI are eligible. 
16. Have alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels >2x upper limit 
of normal (ULN) or bilirubin >1.5x ULN, with the exception of patients with isolated Gilbert’s 
syndrome. 
17. Have an estimated glomerular filtration rate (eGFR; CKD-EPI 2021 equation) <60 mL/min at 
Screening (Visit 1). 
18. Have a thyroid stimulating hormone (TSH) level <0.8x the lower limit of normal or >1.3x ULN. 
Patients with treated thyroid conditions and TSH levels in the aforementioned range will be 
eligible to participate in the study.  
19. Have a Hemoglobin A1c >7.5% ULN at Screening (Visit 1). 
20. Have any other clinically significant abnormalities (significant would include laboratory 
deviations requiring acute medical intervention or further medical evaluation) in laboratory 
results at Screening (Visit 1), including clinical chemistries, hematology, and any clinical 
information that, in the judgment of the Investigator, should preclude a patient’s participation in 
the study. 
21. Females who are either pregnant or breastfeeding. 
22. Site personnel directly affiliated with this study and/or their immediate families. 
23. Have participated in an interventional clinical trial within 90 days prior to Screening (Visit 1).  
Eligibility Criteria for Randomization: 
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1. Continue to meet all inclusion/exclusion criteria,  
2. MADRS total score ≥25 at Baseline (Visit 2), and 
3. ≤25% decrease or increase in MADRS score from Screening (Visit 1) to Baseline (Visit 2). 
Investigational product, dose, and mode of administration: 
TNX-601 ER (tianeptine hemioxalate extended-release tablet) 39.4 mg, taken orally once daily in the 
morning with breakfast and continuing without interruption for 6 weeks of double-blind treatment. 
Duration of Study Participation: 
Up to 5 weeks for screening period, 6 weeks for double-blind treatment period, and 2 weeks for safety 
follow-up period (total up to 13 weeks) 
Reference therapy, dose, and mode of administration: 
Placebo, tablet taken orally once daily in the morning with breakfast and continuing without 
interruption for 6 week of double-blind treatments. Placebo tablets will be devoid of the tianeptine 
hemioxalate but contain the same inactive ingredients as TNX-601 ER and look identical to TNX-601 
ER. 
Criteria for evaluation: 
Primary Efficacy Endpoint: 
The primary efficacy endpoint will be the change from Baseline (Visit 2) in the MADRS total score at 
Week 6.  
Key Secondary Efficacy Endpoints:  
• 
Change from Baseline (Visit 2) in the Clinician Global Impression – Severity (CGI-S) score at 
Week 6 
• 
Change from Baseline (Visit 2) in the Sheehan Disability Scale (SDS) total score at Week 6 
Exploratory Efficacy Endpoints: 
• 
Proportion of patients achieving response, defined as a ≥50% decrease from Baseline (Visit 2) 
in MADRS total score, assessed at Weeks 2, 4, and 6 
• 
Proportion of patients in remission, defined as a MADRS total score ≤10 at Weeks 2, 4, and 6 
• 
Proportion of patients achieving sustained response, defined as a ≥50% decrease from Baseline 
(Visit 2) in MADRS total score at both Weeks 4 and 6 
• 
Proportion of patients with a Clinician Global Impression – Improvement (CGI-I) rating of 
“very much improved” or “much improved” at Weeks 2, 4, and 6 
• 
Mean CGI-I score at Weeks 2, 4, and 6 
• 
Change from Baseline (Visit 2) in Patient Global Impression – Severity (PGI-S) score at Weeks 
2, 4, and 6 
• 
Proportion of patients with a Patient’s Global Impression of Change (PGIC) rating of “very 
much improved” or “much improved” at Weeks 2, 4, and 6  
• 
Mean PGIC score at Weeks 2, 4, and 6 
• 
Change from Baseline (Visit 2) to Week 6 in the Changes in Sexual Functioning Questionnaire 
Short-Form (CSFQ-14) total score in females and in males (analyzed separately) 
• 
Change from Baseline (Visit 2) in the MADRS total score at Week 2 and Week 4 
• 
Change from Baseline (Visit 2) in the CGI-S score at Week 2 and Week 4 
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• 
Change from Baseline (Visit 2) in the SDS total score at Week 2 and Week 4 
• 
Change from Baseline (Visit 2) in the Hamilton Anxiety Rating Scale (HARS) total score at 
Weeks 2, 4, and 6Change from Baseline (Visit 2) in each of the 3 domains (work/school; social 
life; home life or family responsibilities) using the SDS at Weeks 2, 4, and 6 
• 
Proportion of patients with a CGI-S rating of “normal, not at all ill” or “borderline mentally ill” 
at Weeks 2, 4, and 6 
• 
Proportion of patients with a PGI-S rating of “not present”, “very mild”, or “mild” at Weeks 
2, 4, and 6 
Safety and Tolerability: 
• 
Incidence of adverse events (AE) and serious AEs (SAEs) throughout the entire duration of the 
study 
• 
Incidence of AEs associated with abuse liability using the MADDERS® (Misuse, Abuse, 
Diversion Drug Event Reporting System) 
• 
Assessment of physical and neurological examination findings 
• 
Changes from Baseline (Visit 2) in ECG results 
• 
Changes from Baseline (Visit 2) in clinical laboratory test results 
• 
Changes from Baseline (Visit 2) in vital signs and weight 
• 
Indications of increased suicidal ideation or behavior as assessed by the C-SSRS 
• 
Changes from Baseline (Visit 2) in patient-rated CSFQ-14 in males and in females, assessed 
separately 
• 
Change from Baseline (Visit 5/ET) in the Subjective Opiate Withdrawal Scale (SOWS) at the 
Post Study Follow-up (Visit 6). 
Statistical Methods: 
Analysis Populations  
• 
Safety Population (SAFETY): All patients who receive at least 1 dose of investigational 
product, analyzed as treated.  
• 
Intention-to-Treat Population (ITT): All randomized patients who receive at least 1 dose of 
study drug, analyzed as randomized.  
Efficacy Analyses  
The primary efficacy analysis will use a Mixed Model Repeated Measures (MMRM) approach to 
estimate mean change from (Visit 2) in the Total MADRS score evaluated at the Week 6 visit in the 
TNX-601 ER and placebo arms. The model will include all participants in the ITT population, and the 
dependent variable will be the observed change from Baseline (Visit 2) in total MADRS score at each 
postdose visit. Covariates in the model will include the fixed categorical effects of treatment, site, 
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 Statistical Analysis Plan (SAP).  
The primary analysis will be followed by several sensitivity analyses. The key secondary efficacy 
outcomes will be measured and compared between treatment groups and will be adjusted for 
multiplicity using a fixed sequence procedure. Further details on sensitivity and secondary analyses 
can be found in the SAP, as well as the order of the key secondary endpoints. 
Safety Analyses  
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Table 1: 
Study Design and Schedule of Assessments 
Procedures and Evaluations 
Screening 
Baseline 
Double-Blind Treatment 
Period 
Post Study 
Follow-up 
Visit 
1 
2 
3 
4 
5 or 
ET 
6 
Study Week 
-5 to -1 
0 
2 
4 
6 
8 
Study Day 
-35 to -7 
1 
15 ± 2 
29 ± 2 
43 + 2 
57 + 7 
Screening 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Optional Pharmacogenomics consent 
Xg 
 
 
 
 
 
Clinical Trial Subject Registry 
Consent 
Xk 
 
 
 
 
 
Placebo response traininga 
X 
X 
X 
X 
X 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Psychiatric history (MINI 7.0.2) 
X 
 
 
 
 
 
MSI-BPD 
X 
 
 
 
 
 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X  
Demographics and medical history 
X 
 
 
 
Xl 
 
Vital signs, weight, heightb, and 
BMI 
X 
X 
X 
X 
X 
X 
Physical examination, including a 
brief neurological exam 
X 
 
 
 
X 
 
12-lead ECG 
X 
X 
 
 
X 
 
Pregnancy testc  
X 
X 
X 
X 
X 
X 
Urine drug screend 
X 
 
 
 
 
 
Clinical laboratory assessments 
X 
 
 
X 
X 
 
PK  
 
 
 
X 
X 
 
Randomization 
 
X 
 
 
 
 
Study Drug 
 
 
 
 
 
 
Dispense study drug 
 
Xf 
X 
X 
 
 
Study drug return, compliance, and 
accountability 
 
 
X 
X 
X 
 
Optional Pharmacogenomics 
 
 
 
 
 
 
Blood sample collection 
 
Xg 
* 
* 
* 
* 
Efficacy 
 
 
 
 
 
 
MADRS 
X 
X 
X 
X 
X 
 
CGI-S 
 
X 
X 
X 
X 
 
CGI-I 
 
 
X 
X 
X 
 
HARS 
 
X 
X 
X 
X 
 
SDS 
 
X 
X 
X 
X 
 
PGIC 
 
 
X 
X 
X 
 
PGIS 
 
X 
X 
X 
X 
 
Safety 
 
 
 
 
 
 
AEs 
 
X 
X 
X 
X 
X 
MADDERS® 
 
 
Xh 
Xh 
Xh 
Xi 
C-SSRS 
X 
X 
X 
X 
X 
X 
CSFQ-14 
 
X 
 
 
X 
 
SOWS 
 
 
 
 
X 
Xj 
Abbreviations: AE = adverse event; ET = early termination; BMI = Body Mass Index; TSH=Thyroid Stimulating Hormone; CGI-I = Clinical 
Global Impression – Improvement scale; CGI-S = Clinical Global Impression – Severity scale; HARS = Hamilton Anxiety Rating Scale; CSFQ-
14 = Changes in Sexual Functioning Questionnaire Short-Form; C-SSRS = Columbia-Suicide Severity Rating Scales; ECG = Electrocardiogram; 
MADRS = Montgomery-Åsberg Depression Rating Scale; MINI 7.0.2 = Mini International Neuropsychiatric Interview, Version 7.0.2; MSI-BPD 
= McLean Screening Instrument for Borderline Personality Disorder; PGIC = Patient Global Impression of Change; PGIS = Patient Global 
Impression of Severity; PK = pharmacokinetic; SDS = Sheehan Disability Scale; MADDERS® = Misuse, Abuse, Diversion Drug Event 
Reporting System; SOWS = Subjective Opiate Withdrawal Scale. 
a 
A placebo response reduction document is presented to patients by study staff for review and discussion at every in-clinic visit from 
Screening (Visit 1)  through end-of Treatment (Visit 5/ET). 
b 
Height to be measured at Screening (Visit 1)  only. 
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c 
Serum pregnancy test at Screening (Visit 1)  and on-site urine pregnancy test at all other visits for all women of childbearing potential, 
including women who have had bilateral tubal ligation. Serum pregnancy test may be conducted at Investigator’s discretion at End of 
Treatment (Visit 5/ET). 
d 
Performed at Screening (Visit 1) and only at other visits if Investigator suspects drug use or if a prescribed scheduled medication is washed 
out to participate in the study (eg., benzodiazepines, stimulants, opioids). At Screening, both an on-site urine dip-stick and a central laboratory 
sample will be obtained.  
e 
Chemistry, Hematology, HbA1c and TSH at Screening. Chemistry and Hematology only at Visit 4 and Visit5. 
f 
Patient will take first dose of study drug at the clinic at the end of Baseline (Visit 2). 
g 
PGx sample ideally taken at Visit 2 but can be taken at any post-Baseline visit as well (*), noting that Baseline (Visit 2) is best due to 
potential for discontinuation before subsequent visits. 
 
h 
MADDERS® questionnaires will be administered only if any pre-defined AEs and/or DADEs suspect for misuse, abuse or diversion event is 
identified, or any drug accountability issues above the pre-defined threshold are identified. 
i 
MADDERS® Medication Use Survey will be administered to all patients at Visit 6. 
j 
To be completed at +1 day, +2 days, +3 days, +6 days, +9 days, and +12 days at home after the Completion of Treatment, and then in-
person at the Post Study Follow-up visit. 
k  
The Clinical Trial Subject Registry (CTSR) is a mandatory part of the consent process. A site can elect not to participate in the CTSR, with 
approval from the sponsor, and there will be no protocol deviations recorded for leaving it out of the procedures.   
l 
Collection of demographics at Visit 5/ET will only include re-collecting current nicotine, alcohol, and THC usage patterns post double-
blind treatment.  
 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............12 
TABLE OF CONTENTS ...............................................................................................................12 
LIST OF TABLES .........................................................................................................................16 
LIST OF FIGURES .......................................................................................................................17 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5. 
INTRODUCTION ......................................................................................................21 
5.1. 
Brief Summary of Prior Clinical Experience, Dose Rationale, and 
Justification of Study Design ......................................................................................21 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................23 
6.1. 
Primary Objective .......................................................................................................23 
6.2. 
Secondary Objective ...................................................................................................23 
7. 
INVESTIGATIONAL PLAN .....................................................................................23 
7.1. 
Overall Study Design ..................................................................................................23 
7.2. 
Number of Patients and Treatment Assignment .........................................................25 
7.3. 
Study Endpoints ..........................................................................................................25 
7.3.1. 
Primary Efficacy Endpoint .........................................................................................25 
7.3.2. 
Secondary Efficacy Endpoints ....................................................................................25 
7.3.3. 
Exploratory Efficacy Endpoints .................................................................................25 
7.3.4. 
Safety and Tolerability ...............................................................................................26 
7.4. 
Efforts to Minimize Missing Data ..............................................................................26 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................27 
8.1. 
Informed Consent .......................................................................................................27 
8.2. 
Inclusion Criteria ........................................................................................................27 
8.3. 
Exclusion Criteria .......................................................................................................28 
8.4. 
Randomization Criteria ...............................................................................................31 
8.5. 
Prior and Concomitant Medications ...........................................................................31 
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8.5.1. 
Allowed Concomitant Medications ............................................................................32 
8.6. 
Withdrawal Criteria ....................................................................................................32 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................32 
9.1. 
Study Drug Packaging, and Labeling and Storage .....................................................32 
9.2. 
Dosing Instructions .....................................................................................................33 
9.3. 
Dispensing Instructions ..............................................................................................33 
9.4. 
Release of Clinical Study Supplies to the Investigator ...............................................33 
9.5. 
Study Drug Accountability and Reconciliation ..........................................................33 
10. 
STUDY VISITS AND PROCEDURES .....................................................................34 
10.1. 
Visit 1 (Screening: Day -35 to -7) ..............................................................................34 
10.1.1. 
Informed Consent .......................................................................................................34 
10.1.2. 
Screening Overview ....................................................................................................35 
10.1.3. 
Patient Numbering ......................................................................................................35 
10.1.4. 
Screening and Assessments/Procedures .....................................................................35 
10.2. 
Visit 2 (Baseline: Day 1) ............................................................................................36 
10.2.1. 
Pre-Randomization Assessments ................................................................................36 
10.2.2. 
Randomization Criteria ...............................................................................................37 
10.3. 
Visits 3 and 4 (Weeks 2 through 4) ............................................................................38 
10.4. 
Visit 5 (Week 6) ..........................................................................................................39 
10.4.1. 
Early Termination (ET) ..............................................................................................40 
10.4.2. 
Unscheduled Visits .....................................................................................................41 
10.5. 
Visit 6 (Week 8) ..........................................................................................................41 
11. 
STUDY ASSESSMENTS ..........................................................................................42 
11.1. 
Screening Assessments ...............................................................................................42 
11.1.1. 
Psychiatric and Medical History .................................................................................42 
11.2. 
Efficacy Assessments .................................................................................................43 
11.2.1. 
MADRS ......................................................................................................................43 
11.2.2. 
Clinical Global Impression of Severity (CGI-S) ........................................................44 
11.2.3. 
Clinical Global Impression of Improvement (CGI-I) .................................................44 
11.2.4. 
Patient Global Impression of Severity (PGIS) ............................................................44 
11.2.5. 
Patient Global Impression of Change (PGIC) ............................................................45 
11.2.6. 
Sheehan Disability Scale (SDS) .................................................................................45 
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11.2.7. 
Hamilton Anxiety Rating Scale (HARS) ....................................................................45 
11.3. 
Safety Parameters .......................................................................................................46 
11.3.1. 
Adverse Events (AEs) .................................................................................................46 
11.3.2. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................46 
11.3.3. 
Physical Examination .................................................................................................47 
11.3.4. 
Vital Signs, Height, and Weight .................................................................................47 
11.3.5. 
Electrocardiogram (ECG) ...........................................................................................47 
11.3.6. 
Clinical Laboratory Assessments ...............................................................................47 
11.3.7. 
Changes in Sexual Functioning Questionnaire Short-Form (CSFQ-14) ....................49 
11.3.8. 
Misuse, Abuse, Diversion Drug Event Reporting System (MADDERS®) ................50 
11.3.9. 
Subjective Opiate Withdrawal Scale (SOWS) ...........................................................50 
11.4. 
Optional Pharmacogenomic Assessment ....................................................................50 
12. 
DEFINITIONS, RECORDING, AND REPORTING OF ADVERSE 
EVENTS .....................................................................................................................51 
12.1. 
Definition of Adverse Events .....................................................................................51 
12.2. 
Adverse Event Recording ...........................................................................................51 
12.2.1. 
Coding the Adverse Event ..........................................................................................51 
12.2.2. 
Severity of Adverse Event ..........................................................................................51 
12.2.3. 
Relationship of Adverse Events (AEs) to Study Drug ...............................................52 
12.3. 
Serious Adverse Events (SAEs) and Serious Adverse Drug Reactions .....................52 
12.4. 
Pregnancy ...................................................................................................................54 
13. 
STATISTICS ..............................................................................................................55 
13.1. 
Populations for Analysis .............................................................................................55 
13.2. 
Estimate of Sample Size .............................................................................................55 
13.3. 
Assessment of Demographic and Baseline Characteristics ........................................55 
13.4. 
Efficacy Analysis ........................................................................................................55 
13.4.1. 
Efficacy Endpoints ......................................................................................................55 
13.4.2. 
Primary Efficacy Estimand .........................................................................................56 
13.4.3. 
Key Secondary Efficacy Analyses ..............................................................................57 
13.4.4. 
Exploratory Analyses ..................................................................................................58 
13.5. 
Safety Analyses ..........................................................................................................58 
13.6. 
Interim Analyses .........................................................................................................58 
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14. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY .................................................................................59 
14.1. 
Protocol Modifications and Deviations ......................................................................59 
14.2. 
Study Termination ......................................................................................................59 
15. 
ETHICAL CONSIDERATIONS................................................................................60 
15.1. 
Ethical Conduct of the Study ......................................................................................60 
15.2. 
Ethics Committee/Institutional Review Board (EC/IRB) Review .............................60 
15.3. 
Written Informed Consent ..........................................................................................60 
16. 
DATA HANDLING AND RECORDING KEEPING ...............................................61 
16.1. 
Maintaining Privacy and Confidentiality....................................................................61 
16.2. 
Maintaining Essential Clinical Documents ................................................................61 
16.3. 
Data Handling .............................................................................................................62 
16.4. 
Case Report Forms (CRFs) .........................................................................................62 
16.5. 
Screening Records ......................................................................................................62 
16.6. 
Clinical Laboratory Certification ................................................................................63 
16.7. 
Site Monitoring and Tonix’s Right to Review Records .............................................63 
16.8. 
Audits and Inspections ................................................................................................63 
17. 
CONFIDENTIALITY ................................................................................................64 
17.1. 
Protection of Patient Anonymity ................................................................................64 
17.2. 
Confidentiality of Study Information .........................................................................64 
17.3. 
Publication of Data and Protection of Trade Secrets ..................................................64 
18. 
LIST OF REFERENCES ............................................................................................65 
19. 
APPENDICES ............................................................................................................68 
APPENDIX 1 – STABLON SUMMARY OF PRODUCT CHARACTERISTICS 
(MARCH 2018) ..........................................................................................................68 
1 
Stablon Summary of Product Characteristics (Original) ............................................69 
2 
Stablon Summary of Product Characteristics (English Translation) ..........................79 
3 
Stablon Summary of Product Characteristics Certificate of Translation ....................89 
 
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LIST OF TABLES 
Table 1: 
Study Design and Schedule of Assessments ..............................................................10 
Table 2: 
Clinical Laboratory Assessments ...............................................................................49 
Table 3: 
Medical Monitoring Contact Information ..................................................................54 
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LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................24 
 
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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 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression - Improvement Scale  
CGI-S 
Clinical Global Impression – Severity Scale 
CHW 
Cui, Hung, Wang 
CK 
Creatine kinase 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSFQ-14 
Changes in Sexual Functioning Questionnaire Short Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTSR 
Clinical Trial Subject Registry 
DADE 
Drug Accountability Discrepancy Event 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders (version 5) 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GAD 
Generalized Anxiety Disorder 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HARS 
Hamilton Anxiety Rating Scale 
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Abbreviation or 
Specialist Term 
Explanation 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus  
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IND 
Investigational New Drug 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT  
Intention-to-Treat 
IUD 
Intrauterine Device 
IWRS 
Interactive Web Response 
MADDERS® 
Misuse, Abuse, Diversion Drug Event Reporting System 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MAOI 
Monoamine Oxidase Inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDD 
Major Depressive Disorder 
MDE 
Major depressive episode 
MI 
Multiple Imputation 
MINI 7.0.2 
Mini International Neuropsychiatric Interview, Version 7.0.2 
MMRM 
Mixed Model Repeated Measures 
MR 
Modified release 
MR1 
Modified release prototype 1 
MSI-BPD 
McLean Screening Instrument for Borderline Personality Disorder 
RBC 
Red Blood Cell 
PGIC 
Patient Global Impression of Change  
PGIS 
Patient Global Impression - Severity  
PK 
Pharmacokinetic 
PRN 
pro re nata (as needed) 
QTcF 
QT Corrected for Heart Rate using Fridericia’s Formula 
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Abbreviation or 
Specialist Term 
Explanation 
SAD 
Social Anxiety Disorder 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDS 
Sheehan Disability Scale 
SF 
Screen Failure 
SIGMA 
Structured Interview Guide for the MADRS 
SNRI 
Serotonin-Norepinephrine Reuptake Inhibitor 
SOP 
Standard Operating Procedures 
SOWS 
Subjective Opiate Withdrawal Scale 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TBI 
Traumatic Brain Injury 
TCA 
Tricyclic Antidepressant 
TEAE 
Treatment Emergent Adverse Event 
TNX-601 ER 
Tianeptine Hemioxalate Extended-release Tablets 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To evaluate the efficacy of TNX-601 ER (tianeptine hemioxalate extended-release tablets) 
monotherapy in the treatment of major depressive disorder (MDD)  
6.2. 
Secondary Objective 
To evaluate the safety and tolerability of TNX-601 ER (tianeptine hemioxalate extended-release 
tablets) monotherapy in the treatment of MDD. 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a 6-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter 
study to evaluate the efficacy, safety, and tolerability of TNX-601 ER, 39.4 mg monotherapy, on 
symptoms of depression in adult patients with MDD in approximately 30 sites in the United 
States. This study plans to randomize approximately 300 male and female patients aged 18 to 65 
years old (inclusive), with current MDD as defined by DSM-5 criteria. During the 6-week 
double-blind treatment period, patients will receive either TNX-601 ER or placebo in a 1:1 
randomization ratio. After the End of Treatment (Visit 5/ET), there will be a 2-week 
posttreatment safety follow-up period.  
The study will be conducted in 4 periods: Screening (Visit 1), Baseline (Visit 2), Treatment 
(Visits 3-5), and Post Study Follow-up (Visit 6). 
Screening (Visit 1) 
Patients will be consented and assessed for current MDD as defined by DSM-5 diagnostic 
criteria, using the Mini International Neuropsychiatric Interview, Version 7.0.2 (MINI 7.0.2). 
Depression severity will be assessed by MADRS. Eligibility will also depend on medical history, 
physical and neurological examination, use of concomitant medications, and the results of 
laboratory tests (eg, pregnancy and drug screen, liver, kidney, and thyroid function, 
electrocardiogram). 
If a patient meets all eligibility requirements but is currently taking a prohibited medication, 
there will be a Screening Period of up to 35 days for drug tapering and washout. For extenuating 
circumstances and in cases in which a prospective participant is on fluoxetine, the duration of the 
Screening Period may be increased to up to 49 days with Medical Monitor approval. Medication-
free washout time for prohibited medications will be 4 weeks for antidepressants (except for 
fluoxetine, which will be 6 weeks) and atypical antipsychotics. 
Baseline, Randomization, Start of Treatment (Visit 2) 
To ensure continued eligibility prior to randomization, patients will be assessed for all 
inclusion/exclusion criteria, including a MADRS total score of ≥ 25. Patient must also have a 
≤25% decrease or increase in MADRS score from Screening (Visit 1) to Baseline (Visit 2). Any 
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7.2. 
Number of Patients and Treatment Assignment 
A total of approximately 300 patients will be randomized in a 1:1 ratio to treatment with 
once-daily oral TNX-601 ER (tianeptine hemioxalate extended-release tablets) or identical 
placebo tablets, which are devoid of the tianeptine hemioxalate but contain the same inactive 
ingredients present in the active tablets. Randomization will be stratified by study site. 
7.3. 
Study Endpoints 
7.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the change from Baseline (Visit 2) in the MADRS total 
score at Week 6.  
7.3.2. 
Secondary Efficacy Endpoints 
7.3.2.1. 
Key Secondary Efficacy Endpoints 
The efficacy endpoints listed below are considered key secondary endpoints. 
• Change from Baseline (Visit 2) in the Clinician Global Impression – Severity Scale (CGI-S) 
score at Week 6 
• Change from Baseline (Visit 2) in the Sheehan Disability Scale (SDS) total score at Week 6 
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. 
7.3.3. 
Exploratory Efficacy Endpoints 
• Proportion of patients achieving response, defined as a ≥50% decrease from Baseline (Visit 
2) in MADRS total score, assessed at Weeks 2, 4, and 6 
• Proportion of patients in remission, defined as a MADRS total score ≤10 at Weeks 2, 4, and 
6 
• Proportion of patients achieving sustained response, defined as a ≥50% decrease from 
Baseline (Visit 2) in MADRS total score at both Weeks 4 and 6  
• Proportion of patients with a Clinician Global Impression – Improvement Scale (CGI-I) 
rating of “very much improved” or “much improved” at Weeks 2, 4, and 6 
• Mean CGI-I score at Weeks 2, 4, and 6 
• Change from Baseline (Visit 2) in Patient Global Impression of Severity Scale (PGIS) score 
at Weeks 2, 4, and 6 
• Proportion of patients with a Patient Global Impression of Change (PGIC) rating of “very 
much improved” or “much improved” at Weeks 2, 4, and 6  
• Mean PGIC score at Weeks 2, 4, and 6 
• Change from Baseline (Visit 2) to Week 6 in the CSFQ-14 total score in females and in males 
(analyzed separately) 
• Change from Baseline (Visit 2) in the MADRS total score at Week 2 and Week 4 
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• Change from Baseline (Visit 2) in the CGI-S score at Week 2 and Week 4 
• Change from Baseline in the SDS total score at Week 2 and Week 4 
• Change from Baseline (Visit 2) in the Hamilton Anxiety Rating Scale (HARS) total score at 
Weeks 2, 4, and 6 
• Change from Baseline (Visit 2) in each of the 3 domains (work/school; social life; home life 
or family responsibilities) using the SDS at Weeks 2, 4, and 6 
• Proportion of patients with a CGI-S rating of “normal, not at all ill” or “borderline mentally 
ill” at Weeks 2, 4, and 6 
• Proportion of patients with a PGIS rating of “not present”, “very mild”, or “mild” at Weeks 
2, 4, and 6 
7.3.4. 
Safety and Tolerability 
Safety and tolerability will be assessed by: 
• Incidence of AEs and SAEs throughout the entire duration of the study 
• Incidence of AEs associated with abuse liability using MADDERS® 
• Assessment of physical and neurological examination findings 
• Changes from Baseline (Visit 2) in ECG results 
• Changes from Baseline (Visit 2) in clinical laboratory test results 
• Changes from Baseline (Visit 2) in vital signs and weight 
• Indications of increased suicidal ideation or behavior as assessed by the C-SSRS 
• Changes from Baseline in patient-rated CSFQ-14 in males and in females, assessed 
separately  
• Change from Baseline (Visit 5 or End of Treatment) in the SOWS at the Post Study 
Follow-up (Visit 6). 
7.4. 
Efforts to Minimize Missing Data 
It is important to avoid missing data from clinical trials. The following strategies are designed to 
minimize dropouts and missing data in this study: 
1) 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-601 ER may 
be helpful to others in the treatment of MDD. Sites will explain that the study is not 
designed to benefit the individual patient but, rather, can only provide useful 
information for future therapeutics. 
2) Minimizing the burden on patients, with visits scheduled generally every 2 weeks 
(with reasonable visit window flexibility).  
3) Training of site personnel on the importance of minimizing missing data 
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4) 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. 
5) 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 (ICF) before the withdrawal or down titration of any 
medication is initiated. 
Informed consent is documented by means of a written, signed, and dated ICF. Separate written, 
signed informed consent must be obtained if the patient is to participate in the optional 
pharmacogenomic assessment. Additional information is provided in Section 15.3. 
8.2. 
Inclusion Criteria 
Patients enrolled in this study will be volunteer patients. Eligible patients must meet all the 
following inclusion criteria during the screening period: 
1. Male or female aged 18 to 65 years (inclusive).  
2. Have a primary DSM-5 diagnosis of current MDD. 
a) The duration of the current MDE must be at least 12 weeks.  
b) Without psychotic or catatonic features. 
3. Have a MADRS score ≥28 at Screening (Visit 1), ≥25 at Baseline (Visit 2), and a ≤25% 
decrease or increase in MADRS score from Screening (Visit 1) to Baseline (Visit 2). 
4. No acute or potentially confounding medical disorders based on medical history, physical 
and brief neurological exam, vital signs, clinical laboratory tests, and 12-lead ECG 
performed at Screening (Visit 1) and Baseline (Visit 2). 
5. If female, is either not of childbearing potential (defined as postmenopausal for at least 1 year 
or surgically sterile [eg, bilateral oophorectomy or hysterectomy]) or will be practicing one 
of the following methods of birth control throughout the study and for 4 weeks following the 
last dose of the study drug (TNX-601 ER or placebo): 
a) Hormonal methods, such as oral, implantable, injectable, or transdermal contraceptives, 
for a minimum of 1 full cycle (based on the patient’s usual menstrual cycle period) before 
study drug administration; 
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b) Intrauterine device (IUD); 
c) Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal 
jelly or cream); 
d) Bilateral tubal ligation 
e) Partners of vasectomized males in stable relationships; 
f) Females not involved in heterosexual relationships; 
6. Male patients agree to use a reliable method of birth control, as defined above, during the study 
and for at least 4 weeks following the last dose of TNX-601 ER or placebo. 
7. Capable of reading and understanding English and able to provide written informed consent 
to participate. Separate written, signed informed consent will be required if the patient is to 
participate in the optional pharmacogenomic assessment. A decision not to participate in the 
optional pharmacogenomic assessment will not affect the patient’s eligibility for the main 
study. 
8. Are judged to be reliable and agree to keep all appointments for clinic visits, tests, and 
procedures, including venipuncture, and examinations required by the protocol. 
 
8.3. 
Exclusion Criteria 
1. Psychiatric History: 
a) Diagnosis of DSM-5-defined lifetime bipolar disorder (I, II, or unspecified), 
schizophrenia, schizoaffective disorder, MDD with psychotic features, other psychotic 
disorder; antisocial personality disorder; current (past month) obsessive-compulsive 
disorder; current (past month) posttraumatic stress disorder; current (past 3 months) 
anorexia nervosa; lifetime opioid or lifetime sedative-hypnotic use disorders, as 
confirmed by the MINI 7.0.2.  
b) Diagnosis of borderline personality disorder that is known, suspected, or as suggested by 
a score of ≥7 on the McLean Screening Instrument for Borderline Personality Disorder 
(MSI-BPD).  
c) Patients with comorbid generalized anxiety disorder (GAD), social anxiety disorder 
(SAD), or panic disorder are excluded only if the GAD, SAD, or panic disorder is 
considered the primary psychiatric diagnosis, rather than MDD. (If MDD is the primary 
diagnosis, patients with comorbid GAD, SAD, and panic disorder are allowed for 
randomization).  
2. Increased risk of suicide on the basis of 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, or if any of the following results are obtained:  
a) High suicidality based on a MINI 7.0.2 Module B score ≥17 (Screening [Visit 1]); or, 
b) Patient answers YES to either MINI 7.0.2 question B10 or B11 (Screening [Visit 1]); or, 
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c) Patient meets criteria for CURRENT Suicidal Behavior Disorder on the MINI 7.0.2 
(Screening [Visit 1]); or, 
d) A positive response to C-SSRS questions for Type 4 or Type 5 suicide ideation within 
6 months of Screening (Visit 1) or at Baseline (Visit 2); or, 
e) Any suicidal behavior in the past 12 months as identified by the C-SSRS at Screening 
(Visit 1) or between Screening (Visit 1) and Baseline (Visit 2) as identified by the 
C-SSRS at Baseline (Visit 2); or, 
f) A score of >4 on Item 10 of the MADRS at Screening (Visit 1) or Baseline (Visit 2). 
3. Patients with treatment refractory MDD, ie, previously having in their lifetime failed 
≥2 treatments with at least 2 different classes of antidepressants of adequate dose, duration, 
and treatment adherence as assessed by the Investigator at Screening (Visit 1). 
4. Positive urine drug screen results for illicit or abused substances other than cannabis at 
Screening (Visit 1) or Baseline (Visit 2), or history of substance and/or alcohol use disorder 
during the preceding 12 months as evaluated by the MINI 7.0.2 at Screening (Visit 1).  
5. Use of the following concomitant medications:  
a) antidepressants (including St. John’s Wort, S-adenosyl methionine, and/or trazodone used 
as an antidepressant) within 4 weeks of Baseline (Visit 2), except for fluoxetine, which must 
not be within 6 weeks of Baseline (Visit 2); 
b) MAOIs within 4 weeks of Baseline (Visit 2); 
c) oral atypical antipsychotics used for antidepressant augmentation within 4 weeks of 
Baseline (Visit 2). Patients on antipsychotics for other reasons, or patients taking 
conventional antipsychotics are not eligible;  
d) lithium used for antidepressant augmentation within 4 weeks of Baseline (Visit 2). 
Patients on lithium for other reasons are not eligible. 
e) stimulants, benzodiazepines, or buspirone within 1 week of Baseline (Visit 2);  
f) trazodone used as a hypnotic within 1 week of Baseline (Visit 2);  
g) patients on chronic opioids are not eligible. Opioid use is not allowed during the study 
treatment period;  
h) Any use of anticonvulsants other than prophylactic use for migraine. 
6. Have had electroconvulsive treatment, transcranial magnetic stimulation, vagal nerve 
stimulation, or treatment with ketamine or esketamine for MDD. 
7. Have initiated psychotherapy or have had a change in psychotherapy or other nondrug 
therapies (such as acupuncture or hypnosis) within 12 weeks prior to Screening (Visit 1), 
and/or not willing to refrain from initiating such treatment during the course of the study. 
8. A body mass index (BMI) of <18.0 or >40.0 kg/m2. 
9. The patient has a history of sleep apnea that is severe, uncontrolled, or untreated.  Patients 
with mild obstructive sleep apnea (eg, apnea/hypopnea index 5-15), and/or patients, whose 
mild to moderate sleep apnea is well-controlled with CPAP or oral device, are allowed at the 
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discretion of the Investigator. 
10. Have any other clinically significant medical, psychiatric, or social condition prior to 
randomization that, in the opinion of the Investigator, could affect patient safety, preclude 
evaluation of response, interfere with the ability to comply with study procedures, or prohibit 
completion of the study. Examples include hematologic disease or cancer with <5 years 
remission (other than treated carcinoma in situ of the cervix, basal cell carcinoma, or Type 1 
squamous cell carcinoma of the skin). 
11. Diagnosed with clinically significant and currently relevant cardiac disease (eg, arrhythmia 
that is symptomatic or requires treatment, 2nd- or 3rd-degree AV block, complete right or left 
bundle branch block, heart failure, or recent myocardial infarction [within the past 2 years]) 
or QT corrected for heart rate using Fridericia’s formula (QTcF) >450 msec (male) or 
>470 msec (female) on the ECG at Screening (Visit 1). 
12. Evidence of human immunodeficiency virus (HIV) infection based on medical history. 
13. Seizure disorder other than history of childhood febrile seizures. 
14. Hypersensitivity to tianeptine, or any of the excipients in the study drug. 
15. Moderate or severe comorbid traumatic brain injury (TBI) by history. Based on past history 
and Investigator’s judgment, patients with mild TBI are eligible. 
16. Have alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels >2x upper 
limit of normal (ULN) or bilirubin >1.5x ULN, with the exception of patients with isolated 
Gilbert’s syndrome. 
17. Have an estimated glomerular filtration rate (eGFR; CKD-EPI 2021 equation) <60 mL/min at 
Screening (Visit 1). 
18. Have a thyroid stimulating hormone (TSH) level <0.8x the lower limit of normal or >1.3x 
ULN. Patients with treated thyroid conditions and TSH levels in the aforementioned range 
will be eligible to participate in the study.  
19. Have a Hemoglobin A1c >7.5% ULN at Screening (Visit 1). 
20. Have any other clinically significant abnormalities (significant would include laboratory 
deviations requiring acute medical intervention or further medical evaluation) in laboratory 
results at Screening (Visit 1), including clinical chemistries, hematology, and any clinical 
information that, in the judgment of the Investigator, should preclude a patient’s participation 
in the study. 
21. Females who are either pregnant or breastfeeding. 
22. Site personnel directly affiliated with this study and/or their immediate families. 
23. Have participated in an interventional clinical trial within 90 days prior to Screening (Visit 
1).  
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8.4. 
Randomization Criteria 
The following randomization criteria must be satisfied at Baseline (Visit 2) in order for the 
patient to be eligible to continue in the study. Only those patients meeting the following 
randomization criteria are eligible for randomization: 
1. Continue to meet all inclusion/exclusion criteria 
2. MADRS total score ≥25 at Baseline (Visit 2), and 
3. ≤25% decrease or increase in MADRS score from Screening (Visit 1) to Baseline (Visit 2).  
8.5. 
Prior and Concomitant Medications 
Many concomitant psychiatric medications are prohibited during this study because this study 
has been designed to evaluate the safety and efficacy of monotherapy with TNX-601 ER tablets 
for the treatment of MDD. The goal of the study is to recruit patients who are not currently using 
other medications to treat their MDD, 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 MDD may already be taking one or more excluded medications when screened, Principal 
Investigators should use caution when determining whether a patient, in their clinical judgment, 
can be safely withdrawn from current medications that are being used to treat MDD or are 
otherwise excluded from the protocol. 
Eligible patients will not be receiving treatment with antidepressants (including St. John’s Wort, 
S-adenosyl methionine, and/or trazodone used as an antidepressant), mood stabilizers or 
anticonvulsants (other than used for migraine prophylaxis) within 4 weeks of Baseline (Visit 2), 
except for fluoxetine, which must not be within 6 weeks of Baseline (Visit 2). If a patient is receiving 
oral atypical antipsychotics used for antidepressant augmentation, it must not be within 4 weeks 
of the Baseline (Visit 2). Eligible patients will not be receiving antipsychotics for other reasons. 
Eligible patients will also not be receiving stimulants, benzodiazepines, buspirone, or trazodone 
as a hypnotic within 1 week of the Baseline (Visit 2). In cases in which a stimulant is 
discontinued for participation and was positive on Screening (Visit 1) urine toxicology, an 
in-clinic dipstick urine toxicology should be performed prior to randomizing the patient which 
shows the stimulant was successfully washed out. For benzodiazepine washouts with positive 
Screening (Visit 1) urine toxicology, a repeat urine toxicology that is sent to the Central Lab 
must be obtained at least 7 days prior to randomization in an Unscheduled visit showing 
successful washout of the benzodiazepine. The Central Lab is used rather than urine toxicology 
dipsticks because the Central Lab can test a greater number of commonly used benzodiazepines. 
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 as needed (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 2) and throughout 
the 6 weeks of treatment and follow up period in the study. In cases in which opioids are tapered 
and discontinued for the study, an additional urine toxicology by in-clinic dipstick must be 
obtained prior to randomization showing the opioid was successfully washed out. 
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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 4-week 
medication-free period (or 1-week medication-free period, depending on the medication) 
required before Baseline (Visit 2). 
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, 
non-benzodiazepine sleep aids (eg, zolpidem, zaleplon and eszopiclone) and sedating 
antihistamines are allowed on a PRN basis during the study but are to be avoided within 24 hours 
of a clinical visit and generally should not be used more than two to three nights in a row. The 
Investigator should manage the use of these two classes of permissible hypnotics during the 
study, encouraging limited use. The dates on which these are used should be captured in 
concomitant medications at the clinic visits. Chronic nightly use should be avoided whenever 
possible.  
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. 
Sites will collect data on all concomitant medications (other than antidepressants) taken within 
30 days of screening. 
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 10.4.1. 
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 drug bottles will be labeled minimally with the following information:  study 
number TNX-TI-M201, sponsor name and address, bottle number, quantity, storage conditions, 
usage instructions, and caution statements for investigational new drug, eg, Caution:  New Drug 
– Limited by United States Law to Investigational Use and Keep Out of Reach of Children and 
Pets. 
Each study drug bottle will contain 20 tablets. One bottle will be dispensed to each patient at 
Visit 2 (Baseline), Visit 3 (Week 2), and Visit 4 (Week 4); this will provide the patient with 
20 tablets to cover the 2 weeks of dosing between visits, plus additional tablets to cover loss 
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and/or visit window variability. The patient should be instructed to keep this study drug in a safe 
location out of extreme environmental conditions and out of the reach of children and pets, and 
that this drug 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 the bottle and all unused study drug at each 
clinic visit; unused drug will be counted to assess compliance with study drug treatment. 
Storage of the study drug at the investigational sites should be under locked and secure 
conditions with limited staff access. Study drug should be stored at 15-25°C/59-77°F in a 
temperature/humidity-monitored room. 
9.2. 
Dosing Instructions 
Patients will be instructed to take one tablet of their assigned study drug (TNX-601 ER or 
placebo) orally, each morning and continuing without interruption for 6 weeks. Day 1 study drug 
will be taken in the clinic. They should swallow the tablets whole, and not crush or chew the 
tablets. The tablet should be taken in the morning with breakfast. Patients will be reminded that 
only 1 tablet is allowed per day. Note:  In the event that the patient misses a dose, instruct the 
patient to continue dosing with one (1) tablet the next morning; eg, 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 8.4 ) will be assigned 1 
double-blind treatment bottle at Visit 2 via the Interactive Web Response System (IWRS), with a 
unique, but otherwise random bottle number that is generated when an authorized staff member 
successfully completes randomization procedures. Patients will also be assigned a new treatment 
bottle at Visits 3 and 4 via the IWRS. The bottle numbers provided by the IWRS at these visits 
will tell the site which treatment bottles have been assigned to the patient. 
In the event of loss of study drug, new drug will be provided by the IWRS, when appropriately 
requested by the site and/or the sponsor or designee. 
Study treatments for the double-blind treatment phase are either: 
 
Treatment A: 1 x TNX-601 ER tablet (“TNX-601 ER”) 39.4 mg to be taken orally in the 
morning. 
Or 
Treatment B: 1 x placebo tablet (“placebo”) to be taken orally in the morning 
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 bottle of study drug with them to all study visits. At 
each study visit, the site staff will inspect the drug bottle, and perform a count of the tablets 
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remaining in the bottles and document this in the patient’s record. An assessment of drug 
adherence should be done by the study staff to ensure that the patient understands all dosing 
instructions and is taking the drug 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 bottle. If it is found that the patient is not taking the 
study drug as expected, the patient will be re-counselled 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 Investigator will 
identify if it matches a MADDERS® triggering event and complete the MADDERS® 
Supplemental Drug Accountability Form. Patient should be evaluated by the Investigator for the 
reason for the lower-than-expected tablet number and about potential misuse, abuse, or 
diversion, and the Investigator will address this accordingly. If more than 1 tablet cannot be 
accounted for at any of the visits where drug is returned (Week 2, 4, or 6), 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 1 tablet cannot be accounted for, should be recorded as deviations.  
All study drug, 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. 
10. 
STUDY VISITS AND PROCEDURES 
The overall and detailed schedule for study procedures and visits is provided in Table 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 ICF. This signed ICF will be retained in the 
Investigator’s study file, and the date the patient signed the form will be entered into the CRF. 
The patient will be provided with a copy of his or her signed and dated ICF and will also be 
required to sign all updated informed consents. 
The patient will also be presented with a consent to Clinical Trial Subject Registry (CTSR) 
screening, which is a mandatory part of the consent process. 
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 A site can elect not to participate in the CTSR, with approval from the sponsor, and there will be 
no protocol deviations recorded for leaving it out of the procedures.   
The patient will also be presented with the opportunity to participate in the optional 
pharmacogenomic assessment. If the patient agrees to participate in the optional 
pharmacogenomic assessment, a separate signed written ICF must be obtained.  
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 Baseline (Visit 2) 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 Baseline (Visit 2) such that the date of Baseline (Visit 2) is 1 to 5 weeks 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 Baseline (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  
(eg, 202-012) by the IWRS. A screening log or system documenting the following information 
will be recorded and maintained, and will include the patient’s year of birth, 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 
• Review placebo response training with patient 
• Obtain demographics, including alcohol, nicotine/tobacco (smoking, vaping and/or 
chewing), and marijuana use 
• Obtain medical history  
• Obtain prior and current medication history, including all prior MDD therapies and other 
treatments for psychiatric indications  
• Obtain psychiatric history  
o MINI 7.0.2 
o MSI-BPD 
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• MADRS, Structured Interview Guide for the MADRS (SIGMA) version); total score of 
≥28 required at Screening (Visit 1) 
• Perform physical examination, including a brief neurological examination  
• Obtain vital signs, height, weight, and BMI 
• Draw samples for clinical laboratory tests: 
o Blood for chemistry, hematology, HbA1c, thyroid stimulating hormone (TSH)  
o Blood for serum pregnancy test (for women of child-bearing potential) 
o Urine for Drug Screen (central laboratory) 
• Conduct 12-lead ECG 
• Administer C-SSRS, Baseline/Screening Version  
• 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 the Medical 
Monitor or delegate, eligible patients will return to the clinic for Baseline (Visit 2). 
There is no requirement for Follow-Up visits for patients who are SFs. Patients who fail to 
qualify should have their medication adjusted, as appropriate, per the judgment of the 
Investigator and be released from the clinic.  
Patients that are determined to be a screen fail may be re-screened based on Medical Monitor 
approval.  
10.2. 
Visit 2 (Baseline: Day 1) 
Baseline (Visit 2) should be scheduled 7 to 35 days after Screening (Visit 1). If the patient meets 
all randomization criteria, the patient will be randomized via the IWRS system to receive double-
blind study drug. 
10.2.1. 
Pre-Randomization Assessments 
The following assessments must be completed at Baseline (Visit 2) to confirm that the patient is 
eligible for randomization. Upon arrival at the clinic, the following assessments should be done, 
in the following general order: 
• Assess occurrence of AEs 
• Update medical history (with changes since screening noted) 
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• Assess changes in concomitant medications 
• Obtain vital signs and weight 
• Review placebo response training with patient 
• Administer MADRS. Total score must be ≥25 at Baseline (Visit 2), and there must be 
≤25% decrease or increase in MADRS score from Screening (Visit 1) to Baseline 
(Visit 2). 
• Conduct urine drug screen (urine dipstick, only as necessary, if select Screening (Visit 1) 
tests were positive for excluded medications that required discontinuation prior to 
randomization, or if Investigator suspects drug use) 
• Conduct in-clinic urine pregnancy test (for women of child-bearing potential) 
• Collect blood sample for those who consent to participate in the optional 
pharmacogenomics assessment. (The blood draw for this pharmacogenomics assessment 
can be done at any in-clinic visit post-Screening; however, it is preferred that the sample 
is collected at Baseline (Visit 2) whenever possible.) 
• Conduct 12-lead ECG 
• Have the patient complete the following outcome scales (in order): 
o SDS 
o PGIS 
o CSFQ-14 
• Administer the HARS 
• Administer the C-SSRS- Since Last Visit Version  
• Physician to assess CGI-S (needs to be completed once all other assessments are 
available for Investigator to review) 
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) Continue to meet all inclusion/exclusion criteria,  
2) MADRS total score ≥ 25 at Baseline (Visit 2), 
3) ≤25% decrease or increase in MADRS score from Screening (Visit 1) to Baseline 
(Visit 2)  
If the patient does not satisfy these randomization criteria, the patient has failed to qualify for 
this study and should be considered a SF, with the reason documented. With Medical Monitor 
approval, if the patient is otherwise considered a qualified and compliant patient, Baseline (Visit 
2) may be delayed to accommodate situations in which extenuating or short-term circumstances 
do not warrant SF. 
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If the patient does satisfy these randomization criteria, then continue with the following: 
• Randomize the patient via IWRS Randomization System 
• Dispense 2-week supply (1 bottle) of double-blind study drug  
• Review patient instructions regarding study drug dosing (Section 9.2) 
• Have patient take first dose of study drug (Day 1) and observe for 30 min 
• Schedule next study visit 
10.3. 
Visits 3 and 4 (Weeks 2 through 4) 
Visits 3 and 4 are similar study visits that are scheduled to be conducted after 2 and 4 weeks of 
treatment, respectively. Visit 3 should occur on Day 15 ± 2 days and Visit 4 should occur on Day 
29 ± 2 days. 
The following assessments and procedures are scheduled for these visits in the following general 
order: 
• Collect study drug and assess compliance and accountability  
• Assess occurrence of AEs 
• Update concomitant medications 
• Obtain vital signs and weight 
• Review placebo response training with patient 
• Administer the MADRS  
• Conduct urine pregnancy test (for women of child-bearing potential) 
• Visit 4 only: Draw samples, fasting or non fasting, for clinical laboratory tests for: 
o Chemistry and hematology 
o PK 
• Have the patient complete the following outcome scales (in order): 
o SDS 
o PGIS  
o PGIC 
• Administer the HARS 
• Administer C-SSRS - Since Last Visit Version 
• Administer MADDERS® only if any pre-defined AEs and/or Drug Accountability 
Discrepancy Events (DADE) suspect for misuse, abuse, or diversion event is identified 
• Investigator to assess CGI-S and CGI-I (needs to be completed once all other assessments 
are available for Investigator to review) 
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• Dispense new bottle of double-blind study drug as assigned by IWRS 
After all 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 drug back to the clinic at their next visit. 
10.4. 
Visit 5 (Week 6) 
End of Treatment (Visit 5) should occur after 6 weeks of double-blind study drug treatment, 
scheduled at Day 43 + 2 days. The following assessments and procedures are to be completed in 
the following general order: 
• Collect study drug and assess compliance and accountability 
• Assess occurrence of AEs 
• Update concomitant medications  
• Obtain information on current use of alcohol, nicotine/tobacco (smoking, vaping and/or 
chewing), and marijuana 
• Perform physical examination, including a brief neurological examinationObtain vital 
signs and weight 
• Review placebo response training with patient 
• Administer MADRS 
• Conduct urine pregnancy test (for women of child-baring potential). Serum pregnancy 
test may be done at Investigator’s discretion.  
• Draw samples, fasting or non-fasting, for clinical laboratory tests for: 
o Chemistry and hematology 
o PK 
• Conduct 12-lead ECG 
• Have the patient complete the following outcome scales (in order): 
o SDS 
o PGIS, PGIC 
o CSFQ-14 
• Administer the HARS  
• Administer C-SSRS-Since Last Visit Version 
• Administer SOWS and train the patient on how to report the SOWS at Day +1, +2, +3, 
+6, +9 and +12 days via the IWRS  
• Administer MADDERS® only if any pre-defined AEs suspect for misuse, abuse, or 
diversion event is identified, or any drug accountability issues above the pre-defined 
threshold is identified 
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• Physician to assess CGI-S and CGI-I (needs to be completed once all other assessments 
are available for Investigator to review) 
• Schedule the Post Study Follow-up (Visit 6) 
10.4.1. 
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 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 reviewed. Patients who wish to terminate 
their participation in the study early should be strongly encouraged to come to the clinic for an 
ET Visit, and a Follow-up visit. The purpose of the ET 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 drug usage. However, even if there has been a drug lapse, the patient 
should be encouraged to return to the clinic for this visit and should be instructed to return all 
study drug. 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. 
If the patient withdraws from the study, the following assessments and procedures are to be 
completed at this visit in the following general order: 
• Document reason for ET. The Investigator should carefully assess the role of AEs and/or 
lack of efficacy when determining the most accurate reason for the patient’s early 
termination. 
• Collect study drug and assess compliance and accountability 
• Assess occurrence of AEs 
• Update concomitant medications  
• Obtain information on current use of alcohol, nicotine/tobacco (smoking, vaping and/or 
chewing), and marijuana 
• Perform physical examination, including a brief neurological examination 
• Obtain vital signs and weight 
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• Review placebo response training with patient 
• Administer MADRS 
• Conduct urine pregnancy test (for women of child-baring potential). Serum pregnancy 
test may be done at Investigator’s discretion.  
• Draw samples, fasting or non-fasting, for clinical laboratory tests for: 
o Chemistry and hematology 
o PK 
• Conduct 12-lead ECG 
• Have the patient complete the following outcome scales (in order): 
o SDS 
o PGIS, PGIC 
o CSFQ-14 
• Administer the HARS  
• Administer C-SSRS-Since Last Visit Version 
• Administer SOWS and train the patient on how to report the SOWS at Day +1, +2, +3, 
+6, +9 and +12 days via the IWRS 
• Administer MADDERS® only if any pre-defined AEs suspect for misuse, abuse, or 
diversion event is identified, or any drug accountability issues above the pre-defined 
threshold is identified 
• Physician to assess CGI-S and CGI-I (needs to be completed once all other assessments 
are available for Investigator to review) 
• Schedule the Post Study Follow-up (Visit 6) 
Once these assessments have been completed, it should be impressed upon all early terminating 
patients that it is important for safety reasons that they complete the SOWS assessments over the 
next two weeks and return for the Week 8 Post-Study Follow-up visit.  
10.4.2. 
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. 
10.5. 
Visit 6 (Week 8) 
Post Study Follow-up (Visit 6) should occur after 2 weeks from the end of double-blind study 
drug treatment, scheduled at Day 57 + 7 days. The following assessments and procedures are to 
be completed in the following general order: 
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• Assess occurrence of AEs 
• Obtain vital signs and weight 
• Conduct urine pregnancy test (for women of child-bearing potential) 
• Administer the C-SSRS- Since Last Visit Version 
• Administer SOWS 
o Review the patient responses to the SOWS in the foregoing two weeks 
• Administer MADDERS® Medication Use Survey 
Between discontinuation of study drug and the Post Study Follow-up (Visit 6), potential 
withdrawal effects will be assessed at home using the SOWS at +1 day, +2 days, +3 days, 
+6 days, +9 days, and +12 days after the end of Treatment (Visit 5/ET). This includes patients 
who are early terminated.  
11. 
STUDY ASSESSMENTS 
11.1. 
Screening Assessments 
11.1.1. 
Psychiatric and Medical History 
A psychiatric interview using the MINI 7.0.2 (Sheehan et al, 1998), a self-assessed MSI-BPD 
and a comprehensive medical history will be obtained at screening in order to determine whether 
the patient is eligible for enrollment. The MINI 7.0.2 will assess for a lifetime look-back for 
opioid and sedative-hypnotic use disorder rather than the standard 12 months look-back. 
While patients with mild TBI are eligible to participate in the study, moderate and severe TBI are 
excluded. Common traumatic brain injuries result from falls, motor vehicle accidents, assaults, 
and sports injuries. 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 (eg, confusion, disorientation, 
slowed thinking); 
4. Neurological deficits (eg, 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: 
6. Normal structural brain imaging findings 
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7. Loss of consciousness not greater than 30 minutes after injury 
8. Alteration of consciousness not greater than 24 hours after injury 
9. Posttraumatic amnesia not more than 24 hours after injury 
10. 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.) 
Each incidence of traumatic brain injury in a patient’s lifetime history should be assessed using 
these five rule outs for greater than mild TBI, which is exclusionary for the protocol. 
In addition, the past medication history will be reviewed. Any psychiatric medication or MDD 
therapies utilized during the patient’s lifetime should be collected. Responses from the MINI and 
MSI-BPD will serve to document the presence or suspicion of other psychiatric conditions. The 
diagnosis and severity of MDD will be based on the MINI 7.0.2 and MADRS, respectively 
(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 
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. 
MADRS  
The MADRS is a validated, 10-item, clinician-administered depression scale that has been used 
in clinical research since 1979 (Montgomery & Åsberg, 1979). This study will use a structured 
interview version of the MADRS (Structured Interview Guide for the MADRS, SIGMA), which 
was shown to have high interrater reliability (Williams & Kobak, 2008). 
The MADRS will be completed at Screening (Visit 1), Baseline (Visit 2) and after Weeks 2,4, 
and 6 of treatment (Visits 3, 4, and 5, respectively). The 10 items measure the core symptoms 
and cognitive features of clinical depression. This scale has historically been used in 
drug-treatment trials due to its particular sensitivity to detect treatment effects.  
Patients with a Screening (Visit 1) MADRS score of ≥28, ≥25 at Baseline (Visit 2), and a ≤25% 
decrease or increase in MADRS score from Screening (Visit 1) to Baseline (Visit 2) are eligible 
to be randomized. 
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11.2.2. 
Clinical Global Impression of Severity (CGI-S) 
The CGI-S will be completed by an Investigator to assess overall patient severity at the time of 
the assessment. The CGI-S will be completed at Visits 2, 3, 4, and 5 (Baseline, Week 2, 4, and 6, 
respectively). The CGI-S should be completed toward the end of each visit once all assessments 
are available for the Investigator’s review. The Investigator will answer the following question: 
Considering your total clinical experience with this particular population, how mentally ill is the 
patient at this time? 
1 = Normal, not at all ill  
2 = Borderline mentally ill 
3 = Mildly ill 
4 = Moderately ill 
5 = Markedly ill 
6 = Severely ill 
7 = Among the most extremely ill patients 
11.2.3. 
Clinical Global Impression of Improvement (CGI-I) 
The CGI-I will be completed by an Investigator to assess the overall change in the patient’s 
status since Baseline (Visit 2). The CGI-I will be completed at Visits 3, 4, and 5 (Week 2, 4, and 
6, respectively). The CGI-I should be completed toward the end of each visit once all 
assessments are available for the Investigator’s review. The Investigator will answer the 
following question: 
Rate total improvement whether or not in your judgment it is due entirely to drug treatment. 
Compared to his/her condition at Baseline (Visit 2) of TNX-TI-M201, how much has patient 
changed? 
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 Severity (PGIS) 
The PGIS assesses the patients’ overall perception of their condition. This form will be 
completed by the patient at Visits 2, 3, 4, and 5 (Baseline, Week 2, 4, and 6, respectively). The 
patient will answer a single question:  
Please rate the severity of your depression right now: 
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1 = Not present 
2 = Very mild 
3 = Mild 
4 = Moderate 
5 = Moderately severe 
6 = Severe 
7 = Extremely severe 
11.2.5. 
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 Week 2, 4 and 6 of treatment (Visits 
3, 4, and 5, respectively). The patient will answer a single question: 
Since the initiation of study drug, overall, my depression 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 
11.2.6. 
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 2 weeks (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 2 weeks. The SDS scale will be completed by the patient at Baseline (Visit 2), and after 
2, 4, and 6 weeks of treatment (Visits 3, 4, and 5 respectively).  
11.2.7. 
Hamilton Anxiety Rating Scale (HARS) 
The HARS is a widely used and well-validated 14-item clinician-administered scale for assessing 
the severity of symptoms of anxiety (Hamilton, 1959). The scale measures both psychic anxiety 
(mental agitation and psychological distress) and somatic anxiety (physical complaints related to 
anxiety). The HARS will be completed at Baseline (Visit 2) and after 2, 4, and 6 weeks of 
treatment (Visits 3, 4, and 5, respectively).  
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11.3. 
Safety Parameters 
Safety will be assessed by evaluation of AEs; responses on the C-SSRS, and CSFQ-14; clinical 
laboratory test results, physical examination findings, ECG parameters, vital signs, and weight. 
AEs associated with abuse liability of the study drug will be evaluated using the MADDERS®. 
Withdrawal symptoms associated with the study drug after the End of Treatment (Visit 5/ET) 
will be evaluated using the SOWS. 
11.3.1. 
Adverse Events (AEs) 
Patients will be monitored for the occurrence of AEs throughout the study from the time that the 
patient signs an informed consent to their last study visit. 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 drug), 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. 
During the study, all AEs should be followed until resolution, stabilization, or until the subject is 
lost to follow-up. AEs (serious and non-serious) that are ongoing at the last study visit should be 
followed for up to 28 days following the last dose or until one of the above conditions 
(resolution, etc.) is (are) met.  
There are many symptoms associated with MDD 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. 
Additional information regarding definition and reporting requirements for AEs, SAEs, and 
pregnancies is provided in Section 12.2 , Section 12.3, and Section 12.4 respectively  
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” version 
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 (eg, 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” version will be administered, 
and the recall period 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 initiated. 
11.3.3. 
Physical Examination 
A complete physical examination, including a brief neurological examination, will be performed 
at Visit 1 (Screening) and End of Treatment (Visit 5/ET). 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 in addition to the 
brief neurological examination. The physical examination may exclude rectal, genitourinary, and 
breast examinations. 
11.3.4. 
Vital Signs, Height, and Weight 
Vital signs including sitting or supine blood pressure,  heart rate, temperature, and weight will be 
assessed at Visit 1 (Screening), Visit 2 (Baseline), and Visits 3, 4 and 5/ET (after 2, 4, and 6 
weeks of treatment, respectively), as well as at Visit 6.  Height will be measured without shoes at 
Screening (Visit 1) only. The BMI will be a derived variable, based on height and weight entries. 
A BMI of <18.0 or >40.0 kg/m2 is an exclusion criterion. Blood pressure and heart rate should be 
measured after sitting or supine for five minutes at rest. Height will be measured without shoes at 
Screening (Visit 1) only. The BMI will be a derived variable, based on height and weight entries. 
A BMI of <18.0 or >40.0 kg/m2 is an exclusion criterion. 
11.3.5. 
Electrocardiogram (ECG) 
A 12-lead ECG (supine after five minutes rest) will be performed at Screening (Visit 1), Baseline 
(Visit 2) and End of Treatment (Visit 5/ET). The purpose is to 1) exclude patients who have 
either a history of or current evidence of clinically significant and currently relevant cardiac 
disease (eg, significant arrhythmias or heart block, heart failure, or myocardial infarction within 
the past 2 years), a QTcF at Screening >450m/sec (males) or QTcF >470m/sec (females), and 2) 
to determine the effects of the study drug on cardiac intervals. 
The ECG interpretation will be performed by the central reader and confirmed by the 
Investigator, recorded in the CRF as normal, abnormal but not clinically significant, 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 
collected. 
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. 
11.3.6. 
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  Week 4 (Visit 4) and after 6 weeks of treatment (Visit 5), or ET. Clinical laboratory values 
may be repeated prior to randomization in order to confirm exclusionary levels for ALT and/or 
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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 
(Visit 2) for patients washing off excluded medications (eg, benzodiazepines, stimulants, 
opioids), 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, as well as an on-site urine drug test. If the 
patient has a positive drug screen at Screening (Visit 1) and/or Baseline (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 
Screening (Visit 1) and the results can be explained by the use of current prescription 
medications (eg, benzodiazepines, stimulants, opioids) 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. 
Patients with positive results for benzodiazepines at Screening (Visit 1) will need to come back 
to the clinic for repeat centralized urine drug screen following a minimum of one week off all 
benzodiazepines. And since the results of the repeat urine drug screen must be confirmed 
negative prior to randomization, the Baseline visit (Visit 2) should take place no sooner than 7 
days after the patient’s post-washout urine drug screen.  
Each clinically significant abnormal laboratory value or other clinically meaningful abnormality 
should be followed until the abnormality resolves or until a decision is made that it is not likely 
to resolve. If such abnormalities do not return to normal within a reasonable period, their 
etiology should be identified and Tonix or designee should be notified. Treatment-emergent 
clinically significant abnormalities in laboratory values will be recorded as AEs. 
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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)b 
Mean corpuscular hemoglobin (MCH) 
Blood urea nitrogen (BUN) 
Mean corpuscular volume (MCV) 
Calcium 
Platelet count 
Chloride 
Red blood cell (RBC) count 
Cholesterol (total) 
White blood cell (WBC) 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) 
WBC count 
Sodium 
 
Thyroid stimulating hormone (TSH)c at Screening 
(Visit 1) 
Serum Pregnancy Test at Screeningd 
Estimated glomerular filtration rate (eGFR) 
Urine Pregnancy Test (qualitative dipstick)d 
Hemoglobin A1c at Screening (Visit 1) 
Urine Drug Screene 
Pharmacokinetic (PK) testing 
 
Pharmacogenomic testing (optional; can be obtained at 
any visit post-Screening, including an early 
termination visit other than if the patient withdrew 
consent) 
 
a 
Level greater than 2 times the upper limit of normal is an exclusion (if persistent upon repeat). 
b 
Level greater than 1.5 times the upper limit of normal is an exclusion (if persistent upon repeat), with the exception of patients with isolated 
Gilbert’s syndrome. 
c 
TSH level greater than 1.3 times higher than the upper limit of normal or less than 0.8 times the lower limit of normal is exclusionary at 
Visit 1. 
d 
Pregnancy testing for females of child-bearing potential, including women who have had bilateral tubal ligation. A positive pregnancy test 
is exclusionary (Visit 1 or Visit 2) or mandates withdrawal from the study (all other visits). 
e 
Urine drug screening will be conducted on all patients at Screening (Visit 1) and, if necessary, at Baseline (Visit 2) in patients with a 
positive result for excluded medications requiring washout (eg., benzodiazepines, stimulants, opioids) and who otherwise qualify for the 
study. For patients testing positive at the Screening visit (Visit 1) 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 2) visit and must be negative in order for the patient 
to be eligible for randomization (this will primarily apply to opioids and amphetamines). Patients with positive results for benzodiazepines 
at Screening (Visit 1) will need to come into the clinic for a repeat centralized Urine drug screen following a one-week drug free interval, 
and the Baseline visit (Visit 2) may need to be delayed in order to ensure that the results from the repeat centralized UDS can be confirmed 
negative prior to randomization.  
11.3.7. 
Changes in Sexual Functioning Questionnaire Short-Form (CSFQ-14) 
The CSFQ-14 (Keller et al. 2006) is a 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 6 or ET. (Visit 5/ET). It yields a total 
score, 3 subscales corresponding to phases of the sexual response cycle (ie, desire, arousal, 
orgasm), and 5 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 
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corresponds to greater frequency or enjoyment/pleasure (eg, 1 = never to 5 = every day). For 2 
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 
(eg, 1 = every day to 5 = never). Items 10 and 14 are included in the total score but not in any 
scale score.  
Investigators will ensure that patient receives applicable male or female versions of the 
CSFQ-14.  
11.3.8. 
Misuse, Abuse, Diversion Drug Event Reporting System (MADDERS®) 
The MADDERS® is a structured method to: 
• Identify potential abuse-related events associated with study drug  
• Classify the events according to standardized definitions 
• Identify potential abuse-related events not already classified as an adverse event of 
interest or drug accountability discrepancy. 
The Investigator at each site will be trained to identify related adverse events and drug 
accountability discrepancy. This information is collected throughout the study in real time. If any 
of these events are identified during the study, the Investigator will determine if it matches a 
MADDERS® triggering event. If so, the MADDERS® Supplemental Adverse Event Form or the 
MADDERS® Supplemental Drug Accountability Form will be completed. These events are 
adjudicated by a MADDERS® Adjudication Committee after the patient exits the study. 
In addition to, all participants (regardless of the occurrence of a MADDERS® triggering events) 
will complete the MADDERS® Medication Use Survey on Visit 6. If the participant is lost to 
follow-up prior to Visit 6, the Medication Use Survey should be completed based on the site’s 
knowledge of the participant. 
11.3.9. 
Subjective Opiate Withdrawal Scale (SOWS) 
The SOWS is a self-administered 16-item scale for evaluating opioid withdrawal symptoms 
(Handelsman et al., 1987). The SOWS will be administered at End of Treatment (Visit 5/ET) 
(after 6 weeks of treatment/ET), then completed at home at +1 day, +2 days, +3 days, +6 days, 
+9 days, and +12 after Visit 5/ET, and lastly administered at the Post Study Follow-up (Visit 6).  
The purpose of the first administration of the SOWS at End of Treatment (after 6 weeks of 
treatment or ET) is to establish a “baseline” for withdrawal symptoms. The SOWS is given over 
the next three days (+1, +2, and +3 days) because that is the estimated time for TNX-601 ER to 
be eliminated from the body (5 x 11-hour half-life of MC5, a major metabolite of TNX-601 ER). 
The additional days for the SOWS (+6, +9, +12 days) ensures that the SOWS is given at least 
twice a week between the End of Treatment (Visit 5/ET) and the Post Study Follow-up (Visit 6). 
11.4. 
Optional Pharmacogenomic Assessment 
Patients who meet all criteria for randomization will be eligible to participate in the 
pharmacogenomic assessment. A single blood draw will be collected in one 6mL K2 EDTA tube 
for each participating patient after they have signed a separate ICF for pharmacogenomic 
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assessment. The blood draw for this assessment can be done at any in-clinic visit post-Screening; 
however, it is preferred that the sample is collected at Baseline (Visit 2) whenever possible. The 
blood draw may only be performed after the patient has been confirmed to meet all criteria for 
randomization, and after the patient has reviewed and signed the separate pharmacogenomic 
testing ICF. 
The purpose of this testing is to allow genetic sequencing and analysis for genetic variants 
related to treatment response to TNX-601 ER. It is presumed that unused sample will be stored 
up to 15 years, and potentially utilized to develop a pharmacogenomic test for determining 
likelihood of treatment response to TNX-601 ER. A decision not to participate in optional 
pharmacogenomic testing will not affect the patient’s eligibility for the main study. Patients have 
the right to stop participating at any time during the study or during the time of sample storage, 
and, if a patient decides to withdraw from the pharmacogenomics portion of this study, any 
remaining sample will be destroyed and not used for further research. Data collected before a 
patient’s withdrawal from the pharmacogenomics portion of this study will remain in the 
research database. 
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 
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 study drug, whether or not considered related to the study drug. 
A treatment-emergent AE (TEAE) is an AE that either commenced following initiation of study 
drug or was present prior to study drug 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. 
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• 
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 (AEs) to Study Drug 
The Investigator will assess the potential relationship of the AE to study drug using the following 
descriptions. 
• 
Not Related: This category applies to an AE that is clearly not related to the 
investigational agent/procedure, beyond a reasonable doubt. That is, another cause of the 
event is most plausible; and/or a clinically plausible temporal sequence is inconsistent 
with the onset of the event and the administration of study drug and/or a causal 
relationship is considered biologically implausible. 
• 
Unlikely Related: This category applies to an AE that could reasonably be considered 
caused by something else, and where there is no known or expected response pattern to 
the suspected study drug. 
• 
Possibly Related: This category applies to an AE that follows a reasonable temporal 
sequence from administration of the study drug and that follows a known or expected 
response pattern to the suspected study drug, but that could readily have been produced 
by a number of other factors. 
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. For these and all other SAEs, an SAE report 
form must be completed and sent by facsimile or email to Tonix or its designee(s) within 24 
hours of the site’s initial awareness of the event. These requirements apply equally to all patients, 
regardless of the study phase or the at-risk patient’s treatment assignment or dosage. 
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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  must be reported to Tonix or its designee(s) immediately, 
whether or not it is considered treatment-related.  
SAEs report forms must be submitted to 
 within 24 hours of 
the site/investigator’s awareness of the event via facsimile or email: 
 
 
For questions pertaining to the reporting of SAEs or the completion of SAE documentation, site 
personnel should call the 
 
 
Initial SAE reports must be followed by detailed descriptions. These may include copies of 
hospital case records and other documents when requested. All facsimile and email submissions 
will be confirmed by Rho Product Safety within 1 business day of receipt.   
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Key Secondary Efficacy Endpoints: The efficacy endpoints listed below are considered key 
secondary endpoints. 
• Change from Baseline (Visit 2) in the CGI-S score at Week 6 
• Change from Baseline (Visit 2) in the SDS total score at Week 6 
Exploratory Endpoints:   
• Proportion of patients achieving response, defined as a ≥50% decrease from Baseline (Visit 
2) in MADRS total score, assessed at Weeks 2, 4, and 6 
• Proportion of patients in remission, defined as a MADRS total score <=10 at Weeks 2,4, and 
6 
• Proportion of patients achieving sustained response, defined as a ≥50% decrease from 
Baseline (Visit 2) in MADRS total score at Weeks 4 and 6  
•  
• Proportion of patients with a CGI-I rating of “very much improved” or “much improved” at 
Weeks 2, 4, and 6 
• Mean CGI-I score at Weeks 2, 4, and 6 
• Change from Baseline (Visit 2) in PGIS score at Weeks 2, 4, and 6 
• Proportion of patients with a PGIC rating of “very much improved” or “much improved” at 
Weeks 2, 4, and 6  
• Mean PGIC score at Weeks 2, 4, and 6 
• Change from Baseline (Visit 2) to Week 6 in the CSFQ-14 total score in females and in males 
(analyzed separately) 
• Change from Baseline (Visit 2) in the MADRS total score at Week 2 and Week 4 
• Change from Baseline (Visit 2) in the CGI-S score at Week 2 and Week 4 
• Change from Baseline (Visit 2) in the SDS total score at Week 2 and Week 4 
• Change from Baseline (Visit 2) in the HARS total score at Weeks 2, 4, and 6 
• Change from Baseline (Visit 2) in each of the 3 domains (work/school; social life; home life 
or family responsibilities) using the SDS at Weeks 2, 4, and 6 
• Proportion of patients with a CGI-S rating of “normal, not at all ill” or “borderline mentally 
ill” at Weeks 2, 4, and 6 
• Proportion of patients with a PGIS rating of “not present”, “very mild”, or “mild” at Weeks 
2, 4, and 6 
13.4.2. 
Primary Efficacy Estimand 
Population 
The analysis population will be ITT patients with MDD as defined by the protocol 
inclusion/exclusion criteria.  
Variable 
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The primary endpoint will be the change from Baseline (Visit 2) to Week 6 in the MADRS total 
score. 
Intercurrent Events 
Concomitant medications and all other intercurrent events other than discontinuation will use a 
treatment policy strategy; data will be analyzed as observed. A hypothetical strategy will be 
employed to handle intermittent missing data and discontinuation. Missing data will be imputed 
via MI, and details regarding the MI approach will be described in the SAP. 
Population-Level Summary 
The population-level summary will be the difference in least-square means between treatment 
arms (analyzed as randomized) at Week 6.  
The primary efficacy analysis will use a mixed model repeated measures (MMRM) approach to 
estimate mean change from baseline to Week 6 in the MADRS total score visit in the TNX-601 
ER and placebo arms. The model will include all patients in the ITT population, and the 
dependent variable will be the observed change from baseline in the MADRS total score at each 
post-randomization in-clinic visit. Covariates in the model will include the fixed categorical 
effects of treatment, site, 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 MI, and details regarding the MI approach will be described in the SAP.  
The primary analysis will be followed by several sensitivity analyses. Further details on 
sensitivity analyses can be found in the SAP. 
13.4.3. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints will apply estimands parallel with the primary estimand, 
adjusted for the endpoint in question, but with identical populations and handling of intercurrent 
events. MMRM methodology will be utilized for the continuous secondary endpoints, and 
analyses will be based on the ITT population. The dependent variable will be the observed 
change from baseline in the respective secondary endpoint at each post-randomization visit. 
Covariates in the model will include the fixed categorical effects of treatment, site, visit, and 
treatment by visit interaction, as well as the continuous fixed covariates of baseline score and 
baseline score by visit interaction.  
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 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.  The order in which the 
secondary endpoints are to be tested will be specified in the SAP. 
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 
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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 ITT population. Details on exploratory 
efficacy analyses can be found in the SAP. 
13.5. 
Safety Analyses 
Safety analyses will be performed using the Safety Population. Safety and tolerability will be 
assessed by: 
•    Incidence of AEs and SAEs throughout the entire duration of the study 
• Incidence of AEs associated with abuse liability using the MADDERS®  
• Assessment of physical examination findings 
• Changes from baseline (Visit 2) in ECG results 
• Changes from baseline (Visit 2) in clinical laboratory test results 
• Changes from baseline (Visit 2) in vital signs and weight 
• Indications of increased suicidal ideation or behavior as assessed by the C-SSRS 
• Changes from baseline (Visit 2) in patient-rated CSFQ-14 in males and in females, 
assessed separately 
• Change from baseline Visit 5 or End of Treatment) in the SOWS at the safety 
follow-up visit 
Adverse events will be coded using 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 responses on the CSFQ-14, 
and actual values and changes from baseline in clinical laboratory test results, ECG parameters, 
vital signs, and weight will be summarized using descriptive statistics (n, mean, SD, median, 
minimum, and maximum). AEs associated with abuse liability of the study drug will be 
evaluated using the MADDERS®. Withdrawal symptoms associated with the study drug after the 
End of Treatment (Visit 5/ET) will be evaluated using the SOWS. 
The number of patients with suicidal behaviors, ideations and acts based on the C-SSRS will be 
tabulated by treatment group and listed. Physical examination data will be presented in data 
listings. 
13.6. 
Interim Analyses 
An interim analysis will be performed once approximately 50% of the planned patients have 
enrolled and those patients have either completed the study or discontinued early. The purpose of 
the interim will be to evaluate the study for futility and potentially increase the sample size to 
maintain statistical power conditioned on the results of the first 50% of patients. The study team 
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will only be informed of the recommendation to halt the study for futility, maintain the original 
sample size, or to increase the sample size (by a fixed, pre-specified amount). All 
recommendations by the statistical review committee are non-binding.   
For the primary and key secondary outcomes, the results from before and after the interim will 
be combined with Cui, Hung, Wang (CHW) methodology (Cui, 1999). Full details of the interim 
analysis procedure and steps to maintain treatment blinding of the study team will be described 
in the SAP and the Interim Analysis Charter and finalized prior to execution of the interim 
analysis.  
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 ethics committee (EC)/Institutional Review Board (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. 
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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 (World Medical Association, 2013) 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, International Council on Harmonisation (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 (CFR title 21), any EC requirements relative to clinical studies. As 
required by the United States Food and Drug Administration (FDA), the study drug may not be 
shipped to any participating Investigator until the requisite study documentation has been 
submitted an investigational new drug (IND) application. 
Should a conflict arise, the Investigator will follow whichever law or guideline affords the 
greater protection to the individual patient. The Investigator will also make sure he or she is 
thoroughly familiar with the appropriate administration and potential risks of administration of 
the study drug, as described in this protocol and the Investigator’s Brochure, prior to the 
initiation of the study. 
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, “IRBs.”  This protocol, any protocol amendments, the associated ICFs, 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.  
The patient should also be asked in the ICF for permission for the Principal Investigator or their 
designee to contact the patient’s other personal physicians, as appropriate, concerning 
participation in the study. 
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The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of Human 
Patients,” the Health Insurance Portability and Accountability Act (HIPAA) regulations, and all 
other applicable regulatory requirements. A properly executed written ICF shall be read, signed, 
and dated by each patient prior to entering the trial or prior to performing any study procedure. 
The original signed and dated ICF will be kept on file at the study site. Patients will be given a 
copy of the signed ICF and will be informed of any new developments during the course of the 
study that might influence their continued participation in the study. 
The Investigator or a qualified designee will be available to answer each patient’s questions 
throughout the study, and all questions must be answered to the patient’s satisfaction. If the 
protocol is amended and a revised ICF is introduced during the study, each patient’s further 
consent must be obtained. The new version of the ICF must be approved by the EC, prior to 
subsequently obtaining each patient’s consent. 
Receipt of written informed consent will be documented in each patient’s or potential patient’s 
CRF. The signed ICF must remain in each patient’s study file and must be available for 
verification by study monitors at all times. 
Separate written, signed informed consent must be obtained if the patient is to participate in the 
optional pharmacogenomic assessment. 
16. 
DATA HANDLING AND RECORDING KEEPING 
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. 
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 
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be destroyed without prior written consent from Tonix or its designee. Should the Investigator 
wish to withdraw from the responsibility of keeping the study records, custody must be 
transferred to a person willing to accept the responsibility. Tonix must be notified in writing in 
advance if a custodial change is to occur. It is important that the Investigator remain ready to 
provide background information from the archived study records on request. 
The sponsor or designee will maintain adequate study records for at least 2 years after the last 
approval of a marketing application or for at least 2 years after clinical development of the study 
drug for the indication being studied has been discontinued. After that period, the sponsor will be 
contacted to determine whether the study records will be forwarded to the sponsor, destroyed, or 
kept at the location of the designee or another facility for a longer period of time. 
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 subject 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 CRO 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 electronic case report form (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’s sex at birth, age at Screening (Visit 1), and unique patient identification numbers, 
whether they passed or failed screening, and, if they failed, the reason for SF. 
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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 or 
initials, but only by their sex at birth and age at Screening (Visit 1), and the assigned study 
identification numbers. The Investigator should keep a separate record of the patient initials, 
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 (eg, written ICFs). 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. 
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 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 
patients involved or their legal guardians. Tonix retains authority to delete any of its confidential 
information from such disclosures. 
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18. 
LIST OF REFERENCES 
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European Psychiatry: The Journal of the Association of European Psychiatrists 1996;11 (5): 
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Conway CR, Gebara MA, Walker MC, Lessov-Schlaggar CN, Janski AM, Chibnall JT, 
Cristancho P et al. Clinical Characteristics and Management of Treatment-Resistant Depression. 
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Costa e Silva JA, Ruschel SI, Caetano D, Rocha FL, da Silva Lippi FA, Arruda S, and Ozun M. 
Placebo-controlled study of tianeptine in major depressive episodes. Neuropsychobiology. 
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Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999;55(3):853-7. 
Emsley R, Ahokas A, Suarez A, Marinescu D, Dóci I, Lehtmets A, Milanova V, et al. Efficacy 
of tianeptine 25-50 mg in elderly patients with recurrent major depressive disorder: An 8-week 
placebo- and escitalopram-controlled study. The Journal of Clinical Psychiatry. 2018; 79 (4). 
GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and 
national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 
195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease 
Study 2017. Lancet (London, England). 2018; 392: 1789–1858. 
Guelfi JD, Pichot P, and Dreyfus JF. Efficacy of tianeptine in anxious-depressed patients: 
Results of a controlled multicenter trial versus amitriptyline.” Neuropsychobiology. 1989; 22 (1): 
41–48. 
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959; 32:50-55. 
Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two new rating 
scales for opiate withdrawal. American Journal of Alcohol Abuse. 1987; 13: 293-308. 
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Keller A, McGarvey EL, Clayton AH. Reliability and construct validity of the changes in sexual 
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Le Bon O. Contribution of sleep research to the development of new antidepressants. Dialogues 
Clinal Neuroscience. 2005;7(4):305-13. 
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depression: An international, 6-week double-blind study dagger. Human Psychopharmacology. 
2001; 16 (3): 219–27. 
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Fluoxetine. Journal of Affective Disorders. 1999; 56 (2–3): 109–18. 
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neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic 
modulation. Molecular Psychiatry. 2010;15(3): 237-249. 
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and Fluvoxamine in a Prospective, Multicenter, and Descriptive Clinical Study of 344 Patients.” 
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19. 
APPENDICES  
APPENDIX 1 – STABLON SUMMARY OF PRODUCT 
CHARACTERISTICS (MARCH 2018) 
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1 Stablon Summary of Product Characteristics (Original) 
1. DENOMINATION DU MEDICAMENT  
STABLON 12,5 mg, comprimé enrobé.  
2. COMPOSITION QUALITATIVE ET QUANTITATIVE  
Tianeptine (sel de sodium)  12,5 mg  
Pour un comprimé enrobé.  
Excipients à effet notoire : saccharose.  
Pour la liste complète des excipients, voir rubrique 6.1.  
3. FORME PHARMACEUTIQUE  
Comprimé enrobé.  
4. DONNEES CLINIQUES  
4.1. Indications thérapeutiques  
Episodes dépressifs majeurs (c'est-à-dire caractérisés).  
4.2. Posologie et mode d'administration  
Posologie  
La posologie recommandée est de 1 comprimé dosé à 12,5 mg trois fois par jour, matin, midi et 
soir, au début des principaux repas.  
Populations particulières  
Sujets âgés  
L’efficacité et la sécurité de la tianeptine ont été établies chez les patients âgés dépressifs (≥ 65 
ans) (voir rubrique 5.1). Aucune adaptation posologique en rapport avec l’âge n’est nécessaire.  
Chez les patients âgés fragiles (< 55 kg), limiter la posologie à 2 comprimés par jour (voir 
rubrique 5.2).  
Insuffisance rénale  
Chez les patients insuffisants rénaux sévères (ClCr < 19ml/min), limiter la posologie à 2 
comprimés par jour (voir rubrique 5.2).  
Insuffisance hépatique  
Chez les patients atteints de cirrhose sévère (Classe C, Score de Child Pugh), limiter la 
posologie à 2 comprimés par jour (voir rubrique 5.2).  
Chez les patients alcooliques chroniques, qu’ils soient exempts de cirrhose ou atteints de 
cirrhose légère ou modérée, aucune adaptation posologique n'est nécessaire (voir rubrique 
5.2).  
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Population pédiatrique  
La sécurité et l’efficacité de la tianeptine chez les enfants et les adolescents de moins de 18 ans 
n’ont pas été établies. Aucune donnée n’est disponible (voir rubrique 4.4).  
La tianeptine est contre-indiquée chez les enfants et adolescents de moins de 15 ans (voir 
rubrique 4.3).  
Mode d’administration  
Voie orale. Mentions légales complètes  
4.3. Contre-indications  
• 
Hypersensibilité à la substance active ou à l’un des excipients mentionnés à la rubrique 6.1.  
• 
Enfants et adolescents de moins de 15 ans.  
 
4.4. Mises en garde spéciales et précautions d'emploi  
Suicides/idées suicidaires ou aggravation clinique  
La dépression est associée à un risque accru d’idées suicidaires, d’auto-agression et de suicide 
(comportement de type suicidaire). Ce risque persiste jusqu’à obtention d’une rémission 
significative. L’amélioration clinique pouvant ne pas survenir avant plusieurs semaines de 
traitement, les patients devront être surveillés étroitement jusqu’à obtention de cette 
amélioration. L’expérience clinique montre que le risque suicidaire peut augmenter en tout 
début de rétablissement.  
Les patients ayant des antécédents de comportement de type suicidaire ou ceux exprimant des 
idées suicidaires significatives avant de débuter le traitement présentent un risque plus élevé de 
survenue d’idées suicidaires ou de comportements de type suicidaire, et doivent faire l’objet 
d’une surveillance étroite pendant le traitement. Une méta-analyse d’essais cliniques contrôlés 
versus placebo sur l’utilisation d’antidépresseurs chez l’adulte présentant des troubles 
psychiatriques a montré une augmentation du risque de comportement de type suicidaire chez 
les patients de moins de 25 ans traités par antidépresseurs par rapport à ceux recevant un 
placebo. Une surveillance étroite des patients, et en particulier de ceux à haut risque, devra 
accompagner le traitement médicamenteux, particulièrement au début du traitement et lors des 
changements de dose.  
Les patients (et leur entourage) devront être avertis de la nécessité de surveiller la survenue 
d’une aggravation clinique, l’apparition d’idées/comportements suicidaires et tout changement 
anormal du comportement et de prendre immédiatement un avis médical si ces symptômes 
survenaient.  
En cas d'anesthésie générale, il convient d'avertir l'anesthésiste réanimateur et d'arrêter le 
traitement 24 ou 48 heures avant l'intervention.  
En cas d'urgence, l'intervention pourra être néanmoins réalisée sans interruption préalable, 
sous surveillance peropératoire.  
Comme avec tout traitement psychotrope, la prise de ce médicament avec des boissons 
alcoolisées ou médicaments contenant de l’alcool est déconseillée.  
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A l’arrêt du traitement, il est recommandé, comme avec tous les psychotropes, de réduire la 
posologie pendant 7 à 14 jours.  
En cas d’antécédents de pharmacodépendance ou de dépendance à l’alcool, les malades 
doivent être surveillés tout particulièrement pour éviter l’augmentation de la posologie.  
Ne pas dépasser les doses recommandées.  
L’association avec les I.M.A.O. est déconseillée (voir rubrique 4.5). Il est nécessaire de laisser 
un intervalle libre :  
• 
de deux semaines lorsque la tianeptine est utilisé en relais d’un I.M.A.O.,  
• 
de 24 heures lorsque un I.M.A.O. est utilisé en relais de la tianeptine.  
Ce médicament contient du saccharose. Son utilisation est déconseillée chez les patients 
présentant une intolérance au fructose, un syndrome de malabsorption du glucose et du 
galactose ou un déficit en sucrase-isomaltase (maladies héréditaires rares).  
Teneur en sodium  
STABLON contient moins de 1 mmol de sodium (23 mg) par comprimé enrobé et peut donc être 
considéré comme dépourvu de sodium. Mentions légales complètes  
Population pédiatrique  
STABLON est contre-indiqué chez les enfants et adolescents de moins de 15 ans (voir rubrique 
4.3) et ne devrait pas être utilisé chez les adolescents âgés de 15 à 18 ans. Des 
comportements de type suicidaire (tentatives de suicide et idées suicidaires) et de type hostile 
(principalement agressivité, comportement d'opposition et colère) ont été plus fréquemment 
observés au cours des études cliniques chez les enfants et adolescents traités par 
antidépresseurs par rapport à ceux traités par placebo. Si, en cas de nécessité clinique, la 
décision de traiter est néanmoins prise, le patient devra faire l’objet d’une surveillance attentive 
pour détecter l’apparition de symptômes suicidaires. De plus, il n’y a pas de données de 
tolérance à long terme chez l’enfant et l’adolescent, concernant les effets sur la croissance, la 
maturation sexuelle, et le développement cognitif et comportemental.  
4.5. Interactions avec d'autres médicaments et autres formes d'interactions  
Associations déconseillées  
• 
I.M.A.O irréversibles (iproniazide) : en raison des risques de collapsus ou hypertension paroxystique, 
hyperthermie, convulsions, décès.  
4.6. Fertilité, grossesse et allaitement  
Grossesse  
Dans une étude péri- et post-natale, une augmentation des pertes post-implantatoires et post-
natales ont été observées chez les rats à dose maternotoxique (voir rubrique 5.3).  
Il n’existe pas de données ou il existe des données limitées (moins de 300 grossesses) sur 
l’utilisation de la tianeptine chez la femme enceinte.  
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Pour cette raison, il est préférable d’éviter d’utiliser la tianeptine au cours de la grossesse quel 
qu’en soit le terme.  
Le maintien d’un bon équilibre psychique maternel est souhaitable tout au long de la grossesse. 
Si une prise en charge médicamenteuse par tianeptine est nécessaire pour assurer cet 
équilibre, le traitement doit être initié ou poursuivi à dose efficace tout au long de la grossesse 
et si possible en monothérapie et le profil pharmacologique de la molécule doit être pris en 
compte lors de la surveillance du nouveau-né.  
Allaitement  
Une dysfonction de la sécrétion lactique a été observée chez le rat à dose maternotoxique (voir 
rubrique 5.3).  
Les antidépresseurs tricycliques sont excrétés dans le lait maternel, l'allaitement est donc 
déconseillé pendant la durée du traitement.  
Fertilité  
Chez le rat, une étude a montré une diminution des performances reproductives (augmentation 
des pertes pré-implantatoires), à dose maternotoxique. (voir rubrique 5.3).  
L’impact clinique n’est pas connu.  
4.7. Effets sur l'aptitude à conduire des véhicules et à utiliser des machines  
Chez certains patients une baisse de la vigilance est susceptible de se manifester. L'attention 
est donc attirée sur les risques de somnolence attachés à l'emploi de ce médicament 
notamment chez les conducteurs de véhicules et les utilisateurs de machines.  
4.8. Effets indésirables  
Résumé du profil de sécurité :  
Les effets indésirables constatés avec la tianeptine au cours des essais cliniques sont 
d’intensité modérée. Ils consistent principalement en des nausées, constipation, douleurs 
abdominales, somnolence, céphalées, bouche sèche et vertiges. Mentions légales complètes  
Tableau des effets indésirables  
Les effets indésirables suivants ont été observés lors des essais cliniques et/ou de l’utilisation 
post-AMM de la tianeptine et sont classés en fonction de leur fréquence :  
Très fréquent (>1/10); fréquent (>1/100, <1/10); peu fréquent (>1/1000, <1/100); rare 
(>1/10000, <1/1000); très rare (<1/10000), indéterminée (ne pouvant être estimée à partir des 
données disponibles). 
Système Organe-Classe 
(SOC)  
Fréquence  
Effets indésirables  
Fréquent  
Anorexie  
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Système Organe-Classe 
(SOC)  
Fréquence  
Effets indésirables  
Troubles du métabolisme et 
de la nutrition  
Indéterminée* 
Hyponatrémie 
Affections psychiatriques  
Fréquent  
Cauchemars  
Peu fréquent  
Abus, dépendance, en 
particulier chez les sujets de 
moins de 50 ans ayant des 
antécédents de 
pharmacodépendance ou de 
dépendance à l’alcool  
Indéterminée*  
Des cas d’idées et de 
comportements suicidaires ont 
été rapportés durant le 
traitement avec la tianeptine ou 
peu après son arrêt (voir 
rubrique 4.4.) 
Etat confusionnel, 
hallucinations 
Affections du système 
nerveux  
Fréquent  
Insomnie  
Somnolence 
Sensations vertigineuses 
Céphalées 
Présyncope 
Tremblements 
Indéterminée*  
Troubles extrapyramidaux 
Dyskinésie 
Affections cardiaques  
Fréquent  
Tachycardie  
Extrasystoles 
Douleur thoracique 
Affections vasculaires  
Fréquent  
Bouffées de chaleur  
Affections respiratoires, 
thoraciques et médiastinales  
Fréquent  
Dyspnée  
Affections gastro-
intestinales  
Fréquent  
Gastralgies  
Douleurs abdominals 
Bouche sèche 
Nausées 
Vomissements 
Constipation 
Flatulences 
Affections de la peau et du 
tissu sous cutané 
Peu fréquent 
Eruption maculo-papuleuse ou 
érythémateuse 
Prurit 
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Système Organe-Classe 
(SOC)  
Fréquence  
Effets indésirables  
Urticaire 
Indéterminée*  
Acné 
Réactions bulleuses 
exceptionnelles 
Affections musculo-
squelettiques et 
systémiques 
Fréquent  
Myalgie 
Lombalgies 
Troubles généraux et 
anomalies au site 
d’administration 
Fréquent 
Asthénie 
Sensation de gêne au niveau 
de la gorge 
Affections hépato-biliaires 
Indéterminée* 
Augmentation des enzymes 
hépatiques 
Hépatites pouvant être 
exceptionnellement sévères 
*Données post-commercialisation  
Déclaration des effets indésirables suspectés  
La déclaration des effets indésirables suspectés après autorisation du médicament est importante. 
Elle permet une surveillance continue du rapport bénéfice/risque du médicament. Les 
professionnels de santé déclarent tout effet indésirable suspecté via le système national de 
déclaration : Agence nationale de sécurité du médicament et des produits de santé (ANSM) et 
réseau des Centres Régionaux de Pharmacovigilance - Site internet : www.ansm.sante.fr.  
4.9. Surdosage  
Symptômes  
L’expérience relative aux cas d'intoxication aiguë par la tianeptine (quantité maximale: 2250mg, 
ingérée en une seule prise) met principalement en évidence des troubles de la vigilance pouvant 
aller jusqu’au coma, particulièrement en cas d’intoxications multiples.  
Conduite à tenir  
La tianeptine n’a aucun antidote spécifique connu. En cas d’intoxication aiguë, un traitement 
symptomatique et une surveillance de routine doivent être mis en place. Un suivi médical en milieu 
spécialisé est recommandé.  
5. PROPRIETES PHARMACOLOGIQUES  
5.1. Propriétés pharmacodynamiques  
Classe pharmacothérapeutique : AUTRES ANTI-DEPRESSEURS, code ATC : N06AX14.  
Mécanisme d’action  
La tianeptine est un antidépresseur :  
Chez l'animal, la tianeptine possède les caractéristiques suivantes :  
• 
la tianeptine augmente l'activité spontanée des cellules pyramidales de l'hippocampe et en accélère la 
récupération après leur inhibition fonctionnelle,  
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• 
la tianeptine augmente le taux de recapture de la sérotonine par les neurones du cortex et de 
l'hippocampe.  
In vitro, la tianeptine n’a pas d’affinité pour les récepteurs monoaminergiques et n’inhibe pas la 
recapture de la sérotonine (5-HT), de la noradrénaline (NA) ou de la dopamine (DA). La tianeptine 
peut moduler la neuro-transmission glutamatergique synaptique. Mentions légales complètes 
La contribution précise de chaque effet à l'activité antidépressive est inconnue.  
Efficacité et sécurité clinique  
Quatre essais en double aveugle, contrôlés, versus placebo, ont été réalisés pour évaluer l'efficacité 
à court terme de la tianeptine dans le traitement des épisodes dépressifs majeurs chez l’adulte : un à 
doses fixes (37,5 mg, 75 mg), deux avec possibilité d’adaptation posologique à une dose supérieure 
ou inférieure (dose initiale 37,5 mg, puis 25, 37,5 ou 50 mg) et un chez le patient âgé (311 patients 
âgés de 65 ans et plus ; ~100 patients par bras, incluant ~20 patients de plus de 75 ans dans chaque 
bras) avec possibilité d’adaptation posologique à une dose supérieure en fonction de l’amélioration 
après 2 semaines de traitement (dose initiale 25 mg puis 25 mg ou 50 mg). Dans les essais chez 
l’adulte, le critère principal a été l’évolution du score total MADRS par rapport au score initial 
pour les essais à dose fixe ou flexible.  
A la fin du traitement (6 semaines), l’efficacité de la tianeptine était significative dans les deux 
essais à doses flexibles mais pas dans l’essai à doses fixes. Dans un essai, l'imipramine, utilisée 
comme comparateur actif, a permis de démontrer la sensibilité de l’essai.  
Dans l’étude réalisée chez le sujet âgé (étude avec possibilité d’augmenter la posologie), après 8 
semaines de traitement, une efficacité significative de la tianeptine a été démontrée sur le critère 
principal (évolution du score total HAMD par rapport au score initial). Dans cette étude, 
l'escitalopram utilisé comme comparateur actif, a permis de démontrer la sensibilité de l’essai.  
Le maintien de l'efficacité antidépressive a été évalué dans un essai de prévention des rechutes et 
des récidives. Les patients considérés comme répondeurs au traitement par l’investigateur (6 
semaines de traitement « en ouvert » avec la tianeptine à la posologie journalière de 2 à 4 
comprimés soit 25 à 50mg par jour) ont été randomisés à tianeptine ou placebo pour une durée 
supplémentaire de 16,5 mois. La tianeptine a montré une supériorité d’efficacité statistiquement 
significative par rapport au placebo (p <0,001) sur le critère principal de l’essai : la prévention des 
rechutes ou des récidives mesurée par le délai d’apparition de celles-ci. L'incidence des rechutes 
après 6 mois de suivi en double aveugle a été de 6% pour la tianeptine et de 22% pour le placebo. 
L'incidence des rechutes ou des récidives après 18 mois de suivi en double aveugle a été de 16% 
pour la tianeptine et 36% pour le placebo.  
5.2. Propriétés pharmacocinétiques  
Absorption  
L'absorption gastro-intestinale est rapide et complète.  
Distribution  
La distribution est rapide et est associée à une fixation protéique proche de 94 %, principalement à 
l’albumine.  
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Biotransformation  
La tianeptine est fortement métabolisée par le foie, principalement par bêta-oxydation, sans 
implication des CYP450. Son métabolite principal, l’acide pentanoïque (MC5), est actif et moins 
puissant que la tianeptine.  
Élimination  
L'élimination de la tianeptine est caractérisée par une demi-vie terminale courte de 3 h avec la 
plupart des métabolites excrétés dans les urines.  
Patients âgés, très âgés et patients fragiles  
Chez les patients âgés, les concentrations plasmatiques de tianeptine ont été augmentées de 30% et 
celles de MC5 ont été environ doublées après administration unique ou répétée, en comparaison de 
celles de patients plus jeunes (voir rubrique 4.2).  
Chez les patients très âgés (87 ± 5 ans) ou fragiles (45 ± 9 kg), une augmentation significative du 
Cmax et de l’exposition (aire sous la courbe, ASC) à la tianeptine et au MC5 a été observée après 
administration unique (voir rubrique 4.2).  
Patients insuffisants rénaux sévères (CLCR < 19ml/min)  
La pharmacocinétique de la tianeptine reste inchangée mais l’exposition au MC5 est 
approximativement doublée après administration unique et répétée (voir rubrique 4.2).  
Patients atteints de cirrhose hépatique sévère (Classe C, Score de Child-Pugh)  
Les expositions à la tianeptine et au MC5, après l’administration d’une dose de 12,5mg, sont 
augmentées par rapport à celles de patients adultes dépressifs (voir rubrique 4.2).  
En cas de cirrhose plus légère, comme les alcooliques chroniques, les effets sur les paramètres 
pharmacocinétiques sont négligeables (voir section 4.2).  
5.3. Données de sécurité préclinique  
Les données non cliniques issues des études conventionnelles de génotoxicité et de cancérogenèse 
n’ont pas révélé de risque particulier pour l’homme.  
Dans l’étude de fertilité, une augmentation des pertes pré-implantatoires a été observée à la dose 
maternotoxique de 45 mg/kg/jour (soit 12 fois la dose humaine déterminée selon la surface 
corporelle).  
La tianeptine n’est pas tératogène chez les rats et les lapins.  
Dans l’étude péri- et post-natale, une dysfonction de la sécrétion lactique et une augmentation des 
pertes post-implantatoires et post-natales ont été observées chez les rats à la dose maternotoxique 
de 45 mg/kg/jour (soit 12 fois la dose humaine déterminée selon la surface corporelle).  
6. DONNEES PHARMACEUTIQUES  
6.1. Liste des excipients  
Mannitol, amidon de maïs, talc, stéarate de magnésium.  
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Enrobage: éthylcellulose, mono-oléate de glycerol, SEPIFILM SE 700 Blanc (polyvidone, 
carmellose sodique, silice colloïdale anhydre, talc, saccharose, polysorbate 80, dioxyde de titane, 
bicarbonate de sodium), cire d’abeille blanche.  
6.2. Incompatibilités  
Sans objet.  
6.3. Durée de conservation  
36 mois.  
6.4. Précautions particulières de conservation  
Pas de précautions particulières de conservation (zones climatiques I et II).  
A conserver à une température ne dépassant pas 30°C (zones climatiques III et IV).  
6.5. Nature et contenu de l'emballage extérieur  
28 ou 100 comprimés sous plaquettes thermoformées (Aluminium/P.V.C.) (zones climatiques I et 
II).  
28 ou 100 comprimés sous plaquettes thermoformées (Aluminium/P.V.C.) suremballées en sachet 
(zones climatiques III et IV).  
6.6. Précautions particulières d’élimination et de manipulation  
Pas d'exigences particulières.  
7. TITULAIRE/EXPLOITANT DE L’AUTORISATION DE MISE SUR LE MARCHE  
LES LABORATOIRES SERVIER  
50 RUE CARNOT  
92284 SURESNES  
FRANCE  
8. NUMERO(S) D’AUTORISATION DE MISE SUR LE MARCHE  
• 
34009 267 223 5 7 : 28 comprimés sous plaquettes (Aluminium/P.V.C.)  
• 
34009 558 336.0 4 : 100 comprimés sous plaquettes (Aluminium/P.V.C.)  
• 
34009 267 224 1 8 :28 comprimés sous plaquettes (Aluminium/P.V.C.) suremballées en sachet  
• 
34009 579 827 3 7 : 100 comprimés sous plaquettes (Aluminium/P.V.C.) suremballées en sachet.  
9. DATE DE PREMIERE AUTORISATION/DE RENOUVELLEMENT DE 
L’AUTORISATION  
AMM validée en date du 06/02/1987.  
Renouvellement en date du 06/02/2012.  
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10. DATE DE MISE A JOUR DU TEXTE  
Mars 2018  
11. CONDITIONS DE PRESCRIPTION ET DE DELIVRANCE  
Liste I.  
Durée de prescription limitée à 28 jours.  
Prescription en toutes lettres sur ordonnance sécurisée.  
Chevauchement interdit sauf mention expresse du prescripteur portée sur l’ordonnance.  
Conservation d’une copie de l’ordonnance par le pharmacien pendant 3 ans.  
Boîte de 28 : Remboursé Sécurité sociale à 65%. Agréé Collectivités.  
Boîte de 100 : Agréé Collectivités.  
Prix (hors honoraire de dispensation) :  
7,10 € 
(Boîte de 28 comprimés sous plaquettes thermoformées (Aluminium/PVC).  
CTJ : 0,51 € A 0,76 €.  
Au travers des engagements écrits de sa Direction, Servier s’inscrit dans une démarche Qualité 
d’amélioration continue de ses pratiques d’information par démarchage ou prospection visant à la 
promotion des médicaments conformément à la Charte signée par le LEEM et le CEPS et à son 
référentiel de certification émis par la Haute Autorité de Santé (HAS).  
Le collaborateur qui vous a remis le présent document exerce ces missions dans le respect des 
règles de déontologie d’organisation des rencontres avec les professionnels de santé qu’il est à 
même de vous présenter. Ces règles sont également à votre disposition sur notre site internet 
http://servier.fr rubrique « médicaments ».  
Information Médicale et Pharmacovigilance : Servier Affaires Médicales - 35 rue de Verdun, 
92284 Suresnes Cedex- Tel. 01 55 72 60 00  
Appréciation de la qualité des pratiques d'information promotionnelle de nos délégués médicaux : 
qualiteVM@servier.com  
Dans le cadre des activités d’information par démarchage ou prospection visant à la promotion des 
médicaments LES LABORATOIRES SERVIER, situés au 50 rue Carnot, 92284 Suresnes cedex, 
sont amenés à recueillir des données à caractère personnel vous concernant. En application des 
articles 38 et suivants de la loi n° 78-17 du 6 janvier 1978 modifiée, vous pouvez demander à 
accéder, rectifier ou vous opposer au traitement 
18ST2229FF 
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2 Stablon Summary of Product Characteristics (English Translation) 
1. NAME OF THE MEDICINAL PRODUCT  
STABLON 12.5 mg coated tablets. 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION  
Tianeptine (sodium salt)   12.5 mg 
Per coated tablet. 
Excipients with a known effect: sucrose. 
For the full list of excipients, see section 6.1. 
3. PHARMACEUTICAL FORM  
Coated tablet. 
4. CLINICAL PARTICULARS 
4.1. 
Therapeutic indications  
Major depressive episodes. 
4.2. 
Posology and method of administration 
Posology 
The recommended posology is 1 tablet (12.5 mg) three times a day, morning, noon and evening, 
before main meals. 
Special populations 
Elderly patients 
The efficacy and safety of tianeptine have not been established in elderly patients (>65 years) with 
depression (see section 5.1). No age-related dose adjustment is required. 
In fragile elderly patients (<55 kg), limit the dose to 2 tablets a day (see section 5.2). 
Renal impairment 
In patients with severe renal impairment (CrCl <19 ml/min), limit the dose to 2 tablets a day (see 
section 5.2). 
Hepatic impairment 
In patients with severe cirrhosis (Child Pugh score Class C), limit the dose to 2 tablets a day (see 
section 5.2). 
In patients with chronic alcoholism, whether they do not have cirrhosis or have mild or moderate 
cirrhosis, no dose adjustment is necessary (see section 5.2). 
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Paediatric population 
The safety and efficacy of tianeptine have not been established in children and adolescents under 
18 years of age. No data are available (see section 4.4). 
Tianeptine is contraindicated in children and adolescents under 15 years of age (see section 4.3). 
Method of administration 
Oral use. 
4.3. 
Contraindications 
• 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
• 
Children and adolescents under 15 years of age. 
4.4. 
Special warnings and precautions for use 
Suicide/suicidal ideation or clinical worsening 
Depression is associated with an increased risk of suicidal ideation, self-harm and suicide (suicidal 
behaviour). This risk persists until significant remission is obtained. As clinical improvement may 
not be obtained until after several weeks of treatment, patients should be closely monitored until 
this improvement is achieved. Clinical experience shows that suicide risk may increase in the very 
early stages of recovery. 
Patients with a history of suicidal behaviour or those expressing significant suicidal thoughts prior 
to treatment present a higher risk of suicidal ideation or suicidal behaviour and should therefore be 
monitored closely during treatment. A meta-analysis of placebo-controlled clinical trials of the use 
of antidepressants in adults with psychiatric disorders has shown an increased risk of suicidal 
behaviour in patients under 25 years of age treated with antidepressants compared to those 
receiving placebo. Close monitoring of patients, particularly those at high risk, should accompany 
medication, particularly at the start of treatment and when adjusting the dose. 
Patients (and their friends and family) should be advised to monitor for clinical worsening, the 
onset of suicidal ideation/behaviour and abnormal changes in behaviour and to seek medical advice 
immediately if these symptoms occur. 
If the patient requires general anaesthesia, the anaesthetist should be informed and the treatment 
should be withdrawn 24 or 48 hours before the procedure. 
In the event of an emergency, the procedure may however be carried out without prior washout, 
under intraoperative monitoring. 
As with any psychotropic treatment, taking this medicinal product with alcoholic beverages or 
medicinal products containing alcohol is not recommended. 
When discontinuing the treatment, as with all psychotropic medicinal products, it is recommended 
to reduce the dose over 7 to 14 days. 
Patients with a history of drug dependence or alcohol dependence should be monitored particularly 
closely in order to prevent an increase in the posology. 
Do not exceed the recommended doses. 
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Treatment in combination with MAOIs is not recommended (see section 4.5). It is necessary to 
leave a washout period: 
• 
of two weeks when switching from an MAOI to tianeptine, 
• 
of 24 hours when switching from tianeptine to an MAOI. 
This medicine contains sucrose. Use in patients with fructose intolerance, glucose-galactose 
malabsorption or sucrase-isomaltase deficiency (rare hereditary disorders) is not recommended. 
Sodium content 
STABLON contains less than 1 mmol sodium (23 mg) per coated tablet and can therefore be 
considered sodium-free. 
Paediatric population 
STABLON is contraindicated in children and adolescents under 15 years of age (see section 4.3) 
and should not be used in adolescents aged 15 to 18 years. Suicidal behaviour (attempted suicide 
and suicidal ideation) and hostility (primarily aggression, oppositional behaviour and anger) have 
been more frequently observed in clinical studies in children and adolescents treated with 
antidepressants compared to those treated with placebo. If clinical circumstances lead to treatment 
being initiated, the patient should be carefully monitored for the onset of suicidal symptoms. In 
addition, there are no long-term safety data in children and adolescents regarding effects on 
growth, sexual maturity and cognitive and behavioural development. 
4.5. 
Interactions with other medicinal products and other forms of interaction 
Combinations to avoid 
• 
Irreversible MAOIs (iproniazid): due to the risk of collapse or paroxysmal hypertension, hyperthermia, 
convulsions and death. 
4.6. 
Fertility, pregnancy and lactation 
Pregnancy 
In a peri- and postnatal study, an increase in postimplantation and postnatal loss was observed in 
rats at maternally toxic doses (see section 5.3). 
There are no data or limited data (fewer than 300 pregnancies) on the use of tianeptine in pregnant 
women. 
It is therefore preferable to avoid using tianeptine in pregnancy whatever the term. 
Maintaining good maternal psychological stability is desirable throughout pregnancy. If 
pharmaceutical management with tianeptine is necessary to ensure this stability, the treatment must 
be initiated or continued at an effective dose throughout pregnancy and if possible as monotherapy, 
and the pharmacological profile of the drug must be considered during neonatal monitoring. 
Breastfeeding 
Dysfunction in milk secretion has been observed in rats at maternally toxic doses (see section 5.3). 
As tricyclic antidepressants are excreted into breast milk, breastfeeding is not recommended during 
treatment. 
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Fertility 
In rats, a study has shown decreased reproductive performance (increased preimplantation loss) at a 
maternally toxic dose. (see section 5.3). 
The clinical impact is unknown. 
4.7. 
Effects on ability to drive and use machines 
Some patients may experience decreased alertness. Attention is therefore drawn to the risks of 
somnolence associated with the use of this medicinal product, particularly for individuals driving 
vehicles and using machinery. 
4.8. 
Undesirable effects 
Summary of safety profile: 
The undesirable effects observed with tianeptine during clinical trials are of moderate severity. 
They primarily consist of nausea, constipation, abdominal pain, somnolence, headaches, dry mouth 
and dizziness. 
Table of side effects 
The following side effects have been observed in clinical trials and/or post-marketing use of 
tianeptine and are listed according to their frequency: 
Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, 
<1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data). 
System Organ Class (SOC) 
Frequency 
Undesirable effects 
Metabolism and nutrition 
disorders 
Common 
Anorexia 
Not known* 
Hyponatraemia 
Psychiatric disorders 
Common 
Nightmares 
Uncommon 
Abuse, dependence, especially in individuals 
under 50 years of age with a history of alcohol 
dependence or drug dependence 
Not known* 
Cases of suicidal ideation and suicidal 
behaviour have been reported during 
treatment with tianeptine or shortly after its 
discontinuation (see section 4.4). 
Confusional state, hallucinations 
Nervous system disorders 
Common 
Insomnia 
Somnolence 
Dizziness 
Headache 
Presyncope 
Tremors 
Not known* 
Extrapyramidal disorder 
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System Organ Class (SOC) 
Frequency 
Undesirable effects 
Dyskinesia 
Cardiac disorders 
Common 
Tachycardia 
Extrasystoles 
Chest pain 
Vascular disorders 
Common 
Hot flushes 
Respiratory, thoracic and 
mediastinal disorders 
Common 
Dyspnoea 
Gastrointestinal disorders 
Common 
Gastralgia 
Abdominal pain 
Dry mouth 
Nausea 
Vomiting 
Constipation 
Flatulence 
Skin and subcutaneous tissue 
disorders 
Uncommon 
Maculopapular or erythematous rash 
Pruritus 
Urticaria 
Not known* 
Acne 
Dermatitis bullous in exceptional cases 
Musculoskeletal and 
connective tissue disorders 
Common 
Myalgia 
Lower back pain 
General disorders and 
administration site conditions 
Common 
Asthenia 
Lump in the throat sensation 
Hepato-biliary disorders 
Not known* 
Increased liver enzymes 
Hepatitis that may be severe in exceptional 
cases 
*Post-marketing data 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system: 
Agence nationale de sécurité du médicament et des produits de santé (ANSM) and network of 
Regional Pharmacovigilance Centres - Website: www.ansm.sante.fr. 
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4.9. 
Overdose 
Symptoms 
Experience of cases of acute tianeptine poisoning (maximum quantity: 2,250 mg, taken in a single 
dose) has primarily shown impaired alertness that may develop into coma, particularly in cases of 
multiple poisoning. 
Action to take 
Tianeptine has no known specific antidote. In cases of acute poisoning, symptomatic treatment and 
routine monitoring should be initiated. Medical monitoring in a specialist setting is recommended. 
5. PHARMACOLOGICAL PROPERTIES 
5.1 
Pharmacodynamic properties 
Pharmacotherapeutic group: OTHER ANTI-DEPRESSANTS, ATC code: N06AX14. 
Mechanism of action 
Tianeptine is an antidepressant: 
In animals, tianeptine has the following characteristics: 
• 
tianeptine increases the spontaneous activity of pyramidal neurons in the hippocampus and 
speeds up their recovery after functional inhibition, 
• 
tianeptine increases the rate of serotonin reuptake by neurons in the cerebral cortex and 
hippocampus. 
In vitro, tianeptine has no affinity for monoamine receptors and does not inhibit the reuptake of 
serotonin (5-HT), noradrenaline (NA) or dopamine (DA). Tianeptine may modulate synaptic 
glutamate neurotransmission. The precise contribution of each effect to antidepressant activity is 
unknown. 
Efficacy and clinical safety 
Four double-blind, placebo-controlled trials were conducted to assess the short-term efficacy of 
tianeptine in the treatment of major depressive episodes in adults: one at fixed doses (37.5 mg, 75 
mg), two with the ability to adapt to a higher or lower dose (starting dose 37.5 mg, then 25, 37.5 or 
50 mg) and one in elderly patients (311 patients aged 65 years and over; ~100 patients per arm, 
including ~20 patients over 75 years of age in each arm) with the ability to increase the dose 
depending on improvement after 2 weeks of treatment (initial dose of 25 mg then 25 mg or 50 mg). 
In the clinical trials in adults, the primary endpoint was the change from baseline in the total 
MADRS score for the fixed or flexible dose trials. 
At the end of treatment (6 weeks), the efficacy of tianeptine was significant in both the flexible 
dose trials but not in the fixed dose trial. In one trial, imipramine was used as an active comparator, 
making it possible to demonstrate the sensitivity of the trial. 
In the study carried out in elderly patients (with the ability to increase the dose), after 8 weeks of 
treatment, tianeptine was shown to have significant efficacy in relation to the primary endpoint 
(change from baseline in the total HAM-D score). In this study, escitalopram was used as an active 
comparator, making it possible to demonstrate the sensitivity of the trial. 
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Maintenance of antidepressant efficacy was assessed in a trial to prevent relapse and recurrence. 
Patients considered by the Investigator to be treatment responders (6 weeks of “open-label” 
tianeptine treatment at a daily posology of 2 to 4 tablets ie 25-50 mg per day) were randomised to 
tianeptine or placebo for an additional 16.5 months. Tianeptine was shown to have statistically 
significant superiority in efficacy over placebo (p <0.001) for the primary endpoint of the trial: 
prevention of relapse or recurrence as measured by time to onset. The incidence of relapse after 6 
months of double-blind follow-up was 6% for tianeptine and 22% for placebo. The incidence of 
relapse or recurrence after 18 months of double-blind follow-up was 16% for tianeptine and 36% 
for placebo. 
5.2 
Pharmacokinetic properties 
Absorption 
Gastrointestinal absorption is rapid and complete. 
Distribution 
Distribution is rapid and is associated with a level of protein binding close to 94%, primarily to 
albumin. 
Biotransformation 
Tianeptine is extensively metabolised in the liver, primarily by beta-oxidation, without CYP450 
involvement. Its primary metabolite, pentanoic acid (MC5), is active and less potent than 
tianeptine. 
Elimination 
The elimination of tianeptine is characterised by a short terminal half-life of 3 h with most 
metabolites excreted in the urine. 
Elderly, very elderly and fragile patients 
In elderly patients, plasma concentrations of tianeptine were increased by 30% and those of MC5 
approximately doubled after single or repeated administration, in comparison with younger patients 
(see section 4.2). 
In very elderly (87±5 years) or fragile (45±9 kg) patients, a significant increase in Cmax and 
exposure (area under the curve, AUC) to tianeptine and MC5 was observed after single 
administration (see section 4.2). 
Patients with severe renal impairment (CRCL <19 ml/min) 
The pharmacokinetics of tianeptine remain unchanged but exposure to MC5 is approximately 
doubled after single and repeated administration (see section 4.2). 
Patients with severe cirrhosis (Child-Pugh score Class C) 
Exposure to tianeptine and to MC5 after the administration of a single dose of 12.5 mg is increased 
compared to adult patients with depression (see section 4.2). 
In cases of milder cirrhosis, such as patients with chronic alcoholism, the effects on 
pharmacokinetic parameters are negligible (see section 4.2). 
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5.3 
Preclinical safety data 
Non-clinical data from conventional genotoxicity and carcinogenicity studies have identified no 
specific risks for humans. 
In the fertility study, an increase in preimplantation loss was observed at the maternally toxic dose 
of 45 mg/kg/day (12 times the human dose determined by body surface area). 
Tianeptine is not teratogenic in rats and rabbits. 
In the peri- and postnatal study, dysfunction in milk secretion and increased postimplantation and 
postnatal loss were observed in rats at the maternally toxic dose of 45 mg/kg/day (12 times the 
human dose determined by body surface area). 
6. 
PHARMACEUTICAL PARTICULARS 
6.1 
List of excipients 
Mannitol, corn starch, talc, magnesium stearate. 
Coating: ethylcellulose, glycerol monooleate, SEPIFILM SE 700 White (polyvidone, carmellose 
sodium, colloidal anhydrous silica, talc, sucrose, polysorbate 80, titanium dioxide, sodium 
bicarbonate), white beeswax. 
6.2 
Incompatibilities 
Not applicable. 
6.3 
Shelf life 
36 months. 
6.4 
Special precautions for storage 
No special precautions for storage (climate zones I and II). 
Do not store at a temperature above 30°C (climate zones III and IV). 
6.5 
Nature and contents of container 
28 or 100 tablets in blister packs (Aluminium/PVC) (climate zones I and II). 
28 or 100 tablets in blister packs (Aluminium/PVC) overwrapped in sachets (climate zones III and 
IV). 
6.6 
Special precautions for disposal and handling 
No specific requirements. 
7. MARKETING AUTHORISATION HOLDER / EXPLOITANT 
LES LABORATOIRES SERVIER 
50 RUE CARNOT  
92284 SURESNES  
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FRANCE 
8. MARKETING AUTHORISATION NUMBER(S) 
• 
34009 267 223 5 7: 28 tablets in blister packs (Aluminium/PVC) 
• 
34009 558 336.0 4: 100 tablets in blister packs (Aluminium/PVC) 
• 
34009 267 224 1 8: 28 tablets in blister packs (Aluminium/PVC) overwrapped in sachets 
• 
34009 579 827 3 7: 100 tablets in blister packs (Aluminium/PVC), overwrapped in sachets. 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
MA approved on 06/02/1987. 
Renewed on 06/02/2012. 
10. DATE OF REVISION OF THE TEXT 
March 2018 
11. GENERAL CLASSIFICATION FOR SUPPLY 
List I. 
Duration of prescription limited to 28 days. 
The prescription must be written in full on a secure prescription pad. 
Overlapping prohibited unless expressly stated by the prescriber on the prescription. 
A copy of the prescription must be retained by the pharmacist for a period of 3 years. 
Box of 28: 65% social security reimbursement. Approved for hospital use. 
Box of 100: Approved for hospital use. 
Price (excluding dispensing fee): 
€7.10 (Box of 28 tablets in blister packs (Aluminium/PVC). 
Daily cost of treatment: €0.51 to €0.76  
Through the written commitments made by its Management team, Servier is committed to 
continuous quality improvement in the information it provides for solicitation or business 
development purposes for the promotion of medicinal products in accordance with the Charter 
signed by LEEM and CEPS and the certification guidelines issued by the French National 
Authority for Health (HAS). 
The employee who has provided you with this document exercises his/her role in accordance with 
the ethics guidelines for organising meetings with health professionals, a copy of which (s)he can 
also provide. These regulations are also available on our website http://servier.fr in the “medicinal 
products” section. 
Medical Information and Pharmacovigilance: Servier Medical Affairs - 35 rue de Verdun, 92284 
Suresnes Cedex- Tel. 01 55 72 60 00 
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Assessment of the quality of the promotional information activities of our medical sales 
representatives: qualiteVM@servier.com In the context of providing information for solicitation or 
business development purposes for the promotion of medicinal products, LES LABORATOIRES 
SERVIER, located at 50 rue Carnot, 92284 Suresnes Cedex, are required to collect personal data 
about you. Pursuant to Articles 38 et seq. of law no. 78-17 of 6 January 1978 as amended, you can 
request access, rectify or object to the processing of this data by contacting us at the following 
email address: protectiondesdonnees@servier.com. 
18ST2229FF 
 
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3 Stablon Summary of Product Characteristics Certificate of Translation 
 
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SAP_001.pdf: 
Tonix Pharmaceuticals 
Statistical Analysis Plan: TNX-TI-M201
Page 1 of 37
 
STATISTICAL ANALYSIS PLAN 
 
STUDY TITLE: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate 
the Efficacy, Safety, and Tolerability of TNX-601 ER Monotherapy versus Placebo in Patients 
with Major Depressive Disorder (MDD) 
 
PROTOCOL NUMBER:  
TNX-TI-M201 
 
SHORT TITLE: 
UPLIFT 
NCT#: 
NCT05686408 
COMPOUND #: 
 
CLIENT: 
Tonix Pharmaceuticals 
IND 
NUMBER(S): 
 
PREPARED BY: 
 
 
 
 
 
 
 
 
 
 
This document is confidential and proprietary to Tonix Pharmaceuticals. This study is being conducted in 
compliance with good clinical practice, including the archiving of essential documents. Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein will be 
reproduced, published, or otherwise disclosed without the prior written approval of Tonix Pharmaceuticals, 
except that this document may be disclosed to appropriate Institutional Review Boards under the condition that 
they keep the information confidential. 
 
 
 


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Statistical Analysis Plan: TNX-TI-M201
Page 2 of 37
ACKNOWLEDGEMENT AND SIGNATURE SHEET


Tonix Pharmaceuticals 
Statistical Analysis Plan: TNX-TI-M201
Page 3 of 37
VERSION HISTORY 
 
SAP Version 
Version Date 
Change(s) 
Rationale 
 
 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan: TNX-TI-M201
Page 4 of 37
 
 
TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS.......................................................................................7
2.
PURPOSE OF THE ANALYSES ................................................................................9
3.
PROTOCOL SUMMARY ..........................................................................................10
4.
ANALYSIS SAMPLES..............................................................................................12
4.1.
All Patients Population ...............................................................................................12
4.2.
Intention-to-Treat Population .....................................................................................12
4.3.
Safety Population ........................................................................................................12
5.
ESTIMANDS FOR PRIMARY AND KEY SECONDARY EFFICACY 
ENDPOINTS ..............................................................................................................13
5.1.
Primary Efficacy .........................................................................................................13
5.2.
Key Secondary Efficacy .............................................................................................13
6.
STUDY PATIENTS ...................................................................................................15
6.1.
Disposition of Patients ................................................................................................15
6.2.
Demographic and Other Baseline Characteristics ......................................................15
6.3.
Prior and Concomitant Medications/ Therapies .........................................................15
6.4.
Medical History and Physical Examination ...............................................................16
7.
STUDY OPERATIONS .............................................................................................17
7.1.
Protocol Deviations ....................................................................................................17
7.2.
Randomization ............................................................................................................17
7.3.
Measures of Treatment Compliance ...........................................................................17
8.
GENERAL ANAYLSIS AND REPORTING CONSIDERATIONS ........................19
8.1.1.
Study Success .............................................................................................................19
8.1.2.
Multicenter Studies .....................................................................................................19
8.1.3.
Assessment Time Windows ........................................................................................19
8.1.4.
Timing of Analyses .....................................................................................................20
8.1.5.
Multiple Comparisons/Multiplicity ............................................................................20
8.1.6.
Power and Sample Size ..............................................................................................20
9.
ENDPOINT EVALUATION .....................................................................................21
9.1.
Primary Endpoint ........................................................................................................21
9.1.1.
Computation of the Primary Endpoint ........................................................................21


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Statistical Analysis Plan: TNX-TI-M201
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9.1.2.
Primary Analysis of the Primary Endpoint .................................................................22
9.1.3.
Sensitivity Analyses of the Primary Analysis ............................................................22
9.1.4.
Secondary Analyses of the Primary Endpoint ............................................................23
9.2.
Secondary Endpoints ..................................................................................................23
9.2.1.
Key Secondary Endpoints ...........................................................................................23
9.2.2.
Exploratory Endpoints ................................................................................................24
10.
SAFETY EVALUATION ..........................................................................................27
10.1.
Overview of Safety Analysis Methods .......................................................................27
10.2.
Adverse Events ...........................................................................................................27
10.3.
Deaths, Serious Adverse Events, and Other Significant Adverse Events ..................28
10.4.
Clinical Laboratory Evaluation ...................................................................................28
10.5.
Vital Signs, ECGs, Physical Findings, and Other Observations Related to 
Safety ..........................................................................................................................29
10.5.1.
Vital Signs ..................................................................................................................29
10.5.2.
ECGs ...........................................................................................................................29
10.5.3.
Physical Examinations ................................................................................................29
10.5.4.
Other Safety Measures ................................................................................................29
11.
OTHER ANALYSES .................................................................................................32
12.
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .....................33
13.
REFERENCES ...........................................................................................................34
14.
APPENDIX.................................................................................................................35
14.1.
Schedule of Events .....................................................................................................35
14.2.
Random Seeds ............................................................................................................36
15.
ATTACHMENTS .......................................................................................................37
 
 


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Statistical Analysis Plan: TNX-TI-M201
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LIST OF TABLES
Table 1:
List of Abbreviations ....................................................................................................7
 


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Statistical Analysis Plan: TNX-TI-M201
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1.
LIST OF ABBREVIATIONS
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
AESI 
adverse event of special interest 
BID 
twice daily 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CGI-I 
Clinician Global Impression of Improvement 
CGI-S 
Clinician Global Impression of Severity 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CSFQ-14 
Changes in Sexual Functioning Questionnaire Short-Form 
CSR 
clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ECG 
electrocardiogram 
EMA 
European Medicines Agency 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Council on Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IP 
Investigational product 
IU 
international unit 
IWRS 
interactive web response system 
LOE 
lack of efficacy 
LS, LSM 
least square, least square means 
mITT 
modified intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MAR 
missing at random 


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Statistical Analysis Plan: TNX-TI-M201
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MCMC 
Markov Chain Monte Carlo 
MI 
multiple imputation 
MMRM 
Mixed-Effects Model of Repeated Measures 
NDA 
New Drug Application 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
QD 
once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SF 
screen failure 
SOC 
system organ class 
TEAE 
Treatment-Emergent Adverse Event 
US 
United States 
WHO-DD 
World Health Organization Drug Dictionary 
 


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2.
PURPOSE OF THE ANALYSES
This statistical analysis plan (SAP) describes the planned analysis and reporting for Protocol 
TNX-TI-M201 (A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Efficacy, Safety, and Tolerability of TNX-601 ER Monotherapy versus 
Placebo in Patients with Major Depressive Disorder).  
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the US Food and Drug Administration (FDA), European Medicines Agency 
(EMA), and International Council for Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials.  All work planned and reported for this SAP will follow internationally accepted 
guidelines for statistical practice, as published by the American Statistical Association and the 
Royal Statistical Society. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts.  Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data.  Any post-
hoc, or unplanned exploratory analysis performed will be clearly identified as such in the final 
CSR. 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
The reader of this SAP is encouraged to also read the clinical protocol, and other identified 
documents, for details on the planned conduct of this study.  Operational aspects relating to 
collection and timing of planned clinical assessments are not repeated in this SAP unless they are 
relevant to the planned analysis. 


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Statistical Analysis Plan: TNX-TI-M201
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3.
PROTOCOL SUMMARY
This is a 6-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter 
study to evaluate the efficacy, safety, and tolerability of TNX-601 ER, 39.4 mg monotherapy, on 
symptoms of depression in adult patients with MDD in approximately 30 sites in the United 
States. This study plans to randomize approximately 300 male and female patients aged 18 to 65 
years old (inclusive), with current MDD as defined by DSM-5 criteria. During the 6-week 
double-blind treatment period, patients will receive either TNX-601 ER or placebo in a 1:1 
randomization ratio. After the End of Treatment (Visit 5/ET), there will be a 2-week 
posttreatment safety follow-up period.  
The study will be conducted in 4 periods: Screening (Visit 1), Baseline (Visit 2), Treatment 
(Visits 3-5), and Post Study Follow-up (Visit 6). 
Screening (Visit 1) 
Patients will be consented and assessed for current MDD as defined by DSM-5 diagnostic 
criteria, using the Mini International Neuropsychiatric Interview, Version 7.0.2 (MINI 7.0.2). 
Depression severity will be assessed by MADRS. Eligibility will also depend on medical history, 
physical and neurological examination, use of concomitant medications, and the results of 
laboratory tests (eg, pregnancy and drug screen, liver, kidney, and thyroid function, 
electrocardiogram). 
If a patient meets all eligibility requirements but is currently taking a prohibited medication, 
there will be a Screening Period of up to 35 days for drug tapering and washout. For extenuating 
circumstances and in cases in which a prospective participant is on fluoxetine, the duration of the 
Screening Period may be increased to up to 49 days with Medical Monitor approval. Medication-
free washout time for prohibited medications will be 4 weeks for antidepressants (except for 
fluoxetine, which will be 6 weeks) and atypical antipsychotics. 
Baseline, Randomization, Start of Treatment (Visit 2) 
To ensure continued eligibility prior to randomization, patients will be assessed for all 
nt must also have a 
patients not meeting these randomization criteria will be considered a Screen Failure (SF) and 
will not continue in the study. Eligible patients will be randomized in a 1:1 ratio to one of two 
treatment arms (once daily oral TNX-601 ER or placebo). At this visit, study drug will be 
dispensed, and the first dose will be given to eligible patients. 
Double-Blind Treatment Period (Visits 3-5) 
The Treatment Period will last for about 42 days. Several investigator- and patient-rated scales 
and safety assessments (eg, C-SSRS, AEs) will be administered at each visit. At each of the 
3 visits, study drug compliance and accountability will be assessed by collecting previously 
dispensed study drug bottle and counting the remaining tablets. 




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4.
ANALYSIS SAMPLES
Three populations will be utilized for the analyses of data. Disposition of patients will use the All 
Patients Population. The safety analyses will be conducted on the Safety Population. The 
intention-to-treat (ITT) Population will be used for the efficacy analyses.  
4.1. 
All Patients Population 
This includes all patients available in the electronic data capture system; patients will be 
presented by their randomized treatments (if applicable). 
4.2. 
Intention-to-Treat Population 
The ITT population will include all randomized patients who receive at least 1 dose of the 
investigational product. The ITT population is the primary population for efficacy analyses and 
patients will be analyzed based on their randomized treatment. 
4.3. 
Safety Population 
The safety population will include all patients who received at least one dose of study drug. This 
population will be used to summarize the safety data. Patients will be analyzed according to their 
treatment received; if an error in issuing investigational product (IP) occurs and a patient 
receives a mix of treatments, they will be analyzed under the treatment arm with the most IP 
issued to the patient. 


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5.
ESTIMANDS FOR PRIMARY AND KEY SECONDARY 
EFFICACY ENDPOINTS 
5.1. 
Primary Efficacy 
Population 
The target population is individuals with major depressive disorder as defined by the 
inclusion/exclusion criteria. 
Variable 
The primary endpoint will be the change from Baseline (Visit 2) to Week 6 in the MADRS total 
score. 
Intercurrent Events 
Concomitant medications and all other intercurrent events other than discontinuation will use a 
treatment policy strategy; data will be analyzed as observed. A hypothetical strategy will be 
employed to handle intermittent missing data and discontinuation. Patients that that discontinue 
for adverse events or lack of efficacy will be assumed to be representative of patients that would 
not continue treatment and their values will be imputed with multiple imputation (MI) using the 
placebo distribution.  All other missing values, whether intermittent or following discontinuation 
will be assumed to be missing at random and imputed with MI within treatment group.  See 
section 9.1.1 for details of the imputation. 
Population-Level Summary 
The population-level summary will be the difference in least-square means between treatment 
arms (analyzed as randomized) at Week 6.  
The primary efficacy analysis will use a mixed model repeated measures (MMRM) approach to 
estimate mean change from baseline to Week 6 in the MADRS total score visit in the TNX-601 
ER and placebo arms. The model will include all patients in the ITT population, and the 
dependent variable will be the observed change from baseline in the MADRS total score at each 
post-randomization in-clinic visit. Covariates in the model will include the fixed categorical 
effects of treatment, site, visit, and treatment by visit interaction, as well as the continuous fixed 
covariates of baseline score and baseline score by visit interaction. Full details are given in 
section 9.1.2. 
5.2. 
Key Secondary Efficacy  
The efficacy endpoints listed below are considered key secondary endpoints. 
 Change from Baseline (Visit 2) in the CGI-S score at Week 6 
 Change from Baseline (Visit 2) in the SDS total score at Week 6 
The key secondary efficacy endpoints will apply estimands parallel with the primary estimand, 
adjusted for the endpoint in question, but with identical populations and handling of intercurrent 


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events. MMRM methodology will be utilized for the continuous secondary endpoints, and 
analyses will be based on the ITT population. The dependent variable will be the observed 
change from baseline in the respective secondary endpoint at each post-randomization visit. 
Covariates in the model will include the fixed categorical effects of treatment, site, visit, and 
treatment by visit interaction, as well as the continuous fixed covariates of baseline score and 
baseline score by visit interaction. 


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6.
STUDY PATIENTS
6.1. 
Disposition of Patients 
The number and percentage of patients in each analysis population will be summarized. The 
number of patients screened, patients enrolled, and the number and percentage of patients 
completing the study, discontinuing from the study and reasons for discontinuation will also be 
reported. All percentages will be calculated using the number of patients enrolled as the 
denominator. 
6.2. 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics such as age, gender, race/ethnicity, height, weight, 
BMI, and smoking history will be summarized by treatment group (TNX-601 ER and placebo) 
and overall for the ITT and Safety populations. Categorical items will be reported with counts 
and percentages; continuous items will be reported using summary statistics (mean, standard 
deviation (SD), median, minimum, maximum). 
6.3. 
Prior and Concomitant Medications/ Therapies 
Prior medications are defined as medications or therapies initiated prior to the start of the study 
drug and terminated 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 patient receives concurrently with the study 
drug.  These medications will have end dates on or after the first dose date of the study drug if 
they have an end date. In the case of missing or partial dates, medications will be considered 
concomitant unless the available data excludes that possibility. 
All medications will be coded using the World Health Organization Drug Dictionary (WHO-
DD).  Prior and concomitant medications will be summarized by treatment group and by the 
number and percentage of patients taking each medication, classified by using WHO-DD 
Anatomical Therapeutic Chemical Level 3 and preferred term. 
Prior medications for MDD are collected on a separate case report form including whether the 
patient had an efficacy response to the drug and how well they tolerated the drug.  Prior MDD 
drugs will be summarized by preferred term and response; and by preferred term and tolerability. 
Prior psychotherapy will be collected at the screening visit.  The count and percentage of patients 
receiving each type of therapy will be summarized by treatment for each prior therapy; this will 
also be reported for each therapy flagged as ongoing.  All psychotherapy will be presented in a 
listing including the reported start and stop dates of the therapy. 
All medications and therapies will be presented in listings, with prior MDD medications and 
therapies listed separately. 


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6.4.
Medical History and Physical Examination
Medical History will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by system organ class (SOC) and Preferred Term using frequency 
counts and percentages by treatment group.  Physical examination findings will be presented in 
listings. 


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7.
STUDY OPERATIONS
7.1. 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or ICH Good Clinical 
Practice (GCP) requirements. The noncompliance may be either on the part of the patient, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. Protocol deviations will be logged and 
categorized as important or non-important prior to unblinding.  Protocol deviations will be 
summarized by type, status as important/non-important, and by treatment group for the Safety 
population. 
Individual protocol deviations will be listed by patient. 
7.2. 
Randomization 
This is a double-blind study; unless otherwise specified, all study personnel are to remain 
blinded to study drug prior to database lock and final analysis following study unblinding. 
A total of approximately 300 patients will be randomized in a 1:1 ratio to treatment with 
once-daily oral TNX-601 ER (tianeptine hemioxalate extended-release tablets) or identical 
placebo tablets, which are devoid of the tianeptine hemioxalate but contain the same inactive 
ingredients present in the active tablets. Randomization will be stratified by study site. 
The randomization schedule will be computer generated using a permuted block algorithm and 
will randomly allocate study drug to randomization numbers. The randomization numbers will 
be assigned through a central interactive web response system (IWRS) as patients are entered 
into the study. 
7.3. 
Measures of Treatment Compliance 
The treatment duration will be calculated and summarized based on CRF data for first and last 
dose dates (number of days=last dose date  first dose date+1). 
Days of exposure will be based on drug accountability and the number of tablets taken assuming 
 
Compliance will be similarly summarized across all study visits and overall for each treatment 
arm. Study drug compliance as a percentage will be defined as the exposure days defined above 
divided by the total number of expected days on treatment multiplied by 100.  The expected 
number of days will be the drug return date-drug issue date +1 for individual visits and the 
treatment duration as defined above for the overall compliance. 
Compliance will be summarized with descriptive statistics by treatment arm.  The number and 
percentages of patients within certain categories of compliance (e.g. < 60%, 60% to < 80%, 80% 
 


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A listing of drug accountability data based on CRF data will be provided. 


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8.
GENERAL ANAYLSIS AND REPORTING CONSIDERATIONS
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.  
Continuous, quantitative variable summaries will include the number of patients (N) with non-
missing values, mean, standard deviation, median, minimum, and maximum. 
Categorical, qualitative variable summaries will include the frequency and percentage of patients 
who are in the particular category.  In general, the denominator for the percentage calculation 
will be based upon the total number of patients in the study population for the treatment group 
unless otherwise specified. 
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. 
For continuous endpoints where treatment groups are compared via linear models with the 
difference in LS means, the effect size will be calculated and included as a summary statistic 
using the difference in LS means and its standard error, transformed to a standard deviation. 
Study day is defined as assessment date  first dose date +1 for dates after the first dose date and 
assessment date  first dose date for dates prior to the first dose. 
All analyses will be performed using SAS® Software version 9.4 or later. 
8.1.1. 
Study Success 
 
 
 
 
 
 
 
 
  
8.1.2. 
Multicenter Studies 
This is a multicenter study.  Unless otherwise specified, data from all study sites will be pooled 
for all analyses unless otherwise specified. 
8.1.3. 
Assessment Time Windows 
Patients who withdraw/drop out from the study will have the early termination (ET) data 
collected at their ET visit included in the analysis at the closest visit where a given assessment 
should be collected per the schedule of assessments (Week 2, 4, 6), using midpoints between 




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9.
ENDPOINT EVALUATION
9.1. 
Primary Endpoint 
The primary efficacy endpoint will be the change from baseline in the MADRS total score at 
Week 6. 
The MADRS is a validated, 10-item, clinician-administered depression scale. It will be 
completed at Screening (Visit 1), Baseline (Visit 2) and after Weeks 2, 4, and 6 of treatment 
(Visits 3, 4, and 5, respectively). The 10 items measure the core symptoms and cognitive features 
of clinical depression. This scale has historically been used in drug treatment trials due to its 
particular sensitivity to detect treatment effects.  
Patients with a Screening (Visit 1) 
 (Visit 2)
decrease or increase in MADRS score from Screening (Visit 1) to Baseline (Visit 2) are eligible 
to be randomized. 
9.1.1. 
Computation of the Primary Endpoint 
Each item has a severity scale from 0 to 6, with higher scores reflecting more severe symptoms. 
Individual items will be summed to form an overall score (from 0 to 60).  It is not anticipated 
that there will be any missing individual items since the raters will be instructed to complete all 
the assessments.   
A multiple imputation approach will be used to impute data. Missing MADRS overall scores for 
participants in the ITT population will be imputed via multiple imputation (MI).  
 
 
 
 
 
 
   
   
 
   
 
 
 
  
 
 
 
 


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Continuous outcomes included in the list of key secondary outcomes will be handled as above.  
Seeds for the SAS procedures are given in appendix section 14.2. 
9.1.2. 
Primary Analysis of the Primary Endpoint 
Summary statistics (mean, SD, median, minimum, maximum) for the primary efficacy endpoint 
will be reported for the change from the Baseline to week 6 for each of the treatment groups. The 
change from Baseline will be analyzed in an MMRM model for each multiple imputation set 
with fixed effects of treatment, visit, baseline value, treatment by visit interaction, baseline by 
visit interaction and pooled site; an unstructured covariance matrix will be used. Sites with less 
than 5 patients will be pooled into a single site; this covariate may be removed from the model in 
the case of convergence issues. Least square means (LSMs), standard errors, and the LSM 
differences (treatment vs placebo) for each of the 20 MI repeats will be combined using SAS 
procedure MIANALYZE (Rubin, 1976) and  95% CIs and p-values will be reported for each.  
Denominator degrees of freedom will use the Kenward Rogers approach. Should the model with 
unstructured variance fail to converge using the default Newton-Raphson approach, the Fisher 
scores (via the SCORING option of the PROC MIXED statement) will be utilized. Should this 
also fail to converge, then other approaches as detailed in Lu 2010 will be utilized. Once these 
approaches have been exhausted, then the following structures will be used in order with the first 
to converge being selected: heterogeneous Toeplitz, heterogeneous first-order autoregressive, 
Toeplitz, first order autoregressive and compound symmetric will be attempted in that order; in 
these cases, the sandwich estimator (Diggle and Kenward 1994) will be used to estimate the 
standard errors of the fixed effects parameters and the denominator degrees of freedom will 
utilize the DDFM=BETWITHIN option in SAS®. 
9.1.3. 
Sensitivity Analyses of the Primary Analysis 
The following sensitivity analyses may be performed: 
9.1.3.1. 
Missing at Random Multiple Imputation  
For this imputation approach, all values will be imputed under the assumption that they are 
missing at random.  A staged approach as described in section 9.1.1 will be used to first impute 
sporadic missing values with MCMC, then a monotone regression approach for the second stage.  
However, all patients will have missing values imputed within treatment group under the MAR 
assumption. 
9.1.3.2. 
Missing Not at Random Multiple Imputation: All patients imputed from the 
placebo distribution 
For this imputation approach, a staged approach as described in section 9.1.1 will be used to first 
impute sporadic missing values with MCMC, then a monotone regression approach for the 
second stage.  However, all patients will have missing values imputed using the placebo 
distribution as reference.  This will inform the hypothetical possibility that all subjects revert to 
the placebo distribution regardless of their reason for dropout. 


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9.1.3.3. 
Multiple Imputation Tipping Point 
A tipping point analysis will be performed using the primary analysis MI datasets (from section 
9.1.2) and applying an increasing delta (of MADRS score) to the active group until statistical 
significance is no longer achieved.  The delta will only be applied to imputed values; this will be 
done in 0.5 increments on the MADRS total score.  This will only be performed if the primary 
analysis is significant.  This will test the overall robustness of the primary analysis. 
9.1.3.4. 
Current MADRS Version 
The first sixteen subjects were inadvertently assessed under an older version of the MADRS (see 
Clinical Information Amendment dated 25Sep2023 and referenced in section 2).  To assess the 
impact of this, the primary analysis will be repeated with these 16 subjects excluded. 
9.1.4. 
Secondary Analyses of the Primary Endpoint 
In addition to the change from baseline to Week 6 in the MADRS total score, the change from 
baseline at Week 2 and Week 4 will also be reported out of the primary MMRM model described 
in section 9.1.2. 
Additionally, three responder-type analyses of the MADRS total score will be performed: 
 
(Visit 2) in MADRS total score, assessed at Weeks 2, 4, and 6 
 Proportion of patients in remission, defined as a MADRS total score <=10, assessed at 
Weeks 2,4, and 6 
 Proportion of patients achieving sustained response, defined as a 50% decrease from 
Baseline (Visit 2) in MADRS total score at Weeks 4 and 6  
For each, the number and percentage of responders (with response for each as described above) 
and non-responders will be reported, with missing values considered non-responders.  95% CIs 
of the percentages will be given, as well as the difference between treatment groups in 
percentages, its 95% Wald CI, and p-value comparing the groups.  Groups will be tested using a 
-Squared).  In the case of low cell 
 
9.2. 
Secondary Endpoints 
All secondary efficacy analyses will be based on the ITT population.   
9.2.1. 
 Key Secondary Endpoints 
There will be two key secondary endpoints: 
9.2.1.1. 
Change from Baseline (Visit 2) in the CGI-S score at Week 6 
The CGI-S score will be scored 1-7 and treated as a continuous variable. It will be analyzed in a 
manner identical to the primary endpoint (MMRM with MI using an MNAR approach for 
patients dropping for AEs and LOE). 


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Sensitivity analyses will include considering all patient dropouts as missing at random 
(paralleling the approach in section 9.1.3.1) and considering all patient dropouts as missing not at 
random (paralleling the approach in section 9.1.3.2). 
9.2.1.2. 
Change from Baseline (Visit 2) in the SDS total score at Week 6 
For participants that respond to all three questions (work, social life/leisure and home) on the 
SDS, their total score will be the sum of the three items. Participants that do not respond to the 
work/school item because they have not worked or attended school in the recall period for 
reasons unrelated to their disease state will not have that value imputed; to retain the 0 to 30 
1.5. This approach reports the disease impact on the applicable domains. Due to the design of the 
ePRO, participants may both respond to the work/school item and check the box that they have 
not worked or attended school in the recall period for reasons unrelated to their disease state. In 
these instances, the checkbox will supersede the response and the 0-10 score will be censored; as 
above
have either of the other items missing or have work/school item missing but do not check the box 
to indicate that they did not work/attend school will be assigned a missing value. 
The SDS total score will be analyzed in a manner identical to the primary endpoint (MMRM 
with MI using an MNAR approach for patients dropping for AEs and LOE). 
Sensitivity analyses will include considering all patient dropouts as missing at random 
(paralleling the approach in section 9.1.3.1) and considering all patient dropouts as missing not at 
random (paralleling the approach in section 9.1.3.2). 
9.2.2. 
Exploratory Endpoints 
9.2.2.1. 
Continuous Exploratory Endpoints 
Each of the following continuous endpoints will be summarized: 
 Change from Baseline (Visit 2) in the CGI-S score at Week 2 and Week 4 
 Change from Baseline (Visit 2) in the SDS total score at Week 2 and Week 4 
 Change from Baseline (Visit 2) in PGIS score at Weeks 2, 4, and 6 
 Change from Baseline (Visit 2) to Week 6 in the CSFQ-14 total score in females and in 
males (analyzed separately) 
 Change from Baseline (Visit 2) in the HARS total score at Weeks 2, 4, and 6 
 Change from Baseline (Visit 2) in each of the 3 domains (work/school; social life; home 
life or family responsibilities) using the SDS at Weeks 2, 4, and 6 
 Mean PGIC score at Weeks 2, 4, and 6 
 Mean CGI-I score at Weeks 2, 4, and 6 
The CGI-S score and SDS total score at Week 2 and Week 4 will be reported out of the same 
MMRM model used for each of these key secondary endpoints. 


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The PGIS, HARS total score, and SDS domains (work/school; social life; home life or family 
responsibilities) will be analyzed using a model identical to the primary efficacy endpoint, but on 
observed data only, without multiple imputation. Additionally, the primary efficacy and key 
secondary endpoints will be reported out of an MMRM without imputation.   
The CSFQ-14 total score will be summarized with descriptive statistics and compared between 
groups with an ANCOVA with effects for treatment and baseline value. 
The PGIC and the CGI-I will be considered both as responder analyses (see below) and as 
continuous 1-7 values.  For continuous PGIC and the CGI-I, summary statistics (mean, SD, 
median, minimum, maximum) will be reported for each visit for each of the treatment groups. 
They will be analyzed in an MMRM model with fixed effects of treatment, visit, treatment by 
visit interaction, and site; an unstructured covariance matrix will be used. Least square means 
(LSMs), standard errors, and the LSM differences (each treatment vs placebo) with 95% CIs and 
p-values will be reported for each visit. Denominator degrees of freedom will use the Kenward 
Rogers approach. Should the model with unstructured variance fail to converge using the default 
Newton-Raphson approach, the Fisher scores (via the SCORING option of the PROC MIXED 
statement) will be utilized. Should this also fail to converge, then other approaches as detailed in 
Lu 2010 will be utilized. Once these approaches have been exhausted, then the following 
structures will be used in order with the first to converge being selected: heterogeneous Toeplitz, 
heterogeneous first-order autoregressive, Toeplitz, first order autoregressive and compound 
symmetric will be attempted in that order; in these cases, the sandwich estimator (Diggle and 
Kenward 1994) will be used to estimate the standard errors of the fixed effects parameters and 
the denominator degrees of freedom will utilize the DDFM=BETWITHIN option in SAS®. 
9.2.2.2. 
Categorical Secondary Endpoints 
The following categorical endpoints will be tabulated: 
 Proportion of patients with a CGI-
at Weeks 2, 4, and 6 
 
at Weeks 2, 4, and 6  
 Proportion of patients with a CGI-
 
 
Weeks 2, 4, and 6 
For each, at each visit, the number and percentage of patients in each category (without 
dichotomizing) will be reported as well as the number of missing values.  The number and 
percentage of responders (with response for each as described above) and non-responders will be 
reported, with missing values considered non-responders.  95% CIs of the percentages will be 
given, as well as the difference between treatment groups in percentages, its 95% Wald CI, and 
p-value comparing the groups.  Groups will be tested using a difference in proportions Z test 


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-Squared).  In the case of low cell counts (<5 expected in a given 
 
9.2.2.3. 
Subgroup Analyses 
Subgroup analyses will be conducted for the primary and key secondary endpoints.  These will 
report the descriptive statistics within each subgroup for observed data without imputation and 
(if feasible) fit the primary MMRM model and report the LSmeans & 95% CIs for each 
treatment and timepoint.  Treatment differences at each timepoint will be reported with the 
LSmean difference and 95% CI, if estimable.   
 
Subgroups will include: 
 Age (>40 years old, <=40 Years old) 
 Sex at birth (Male/ Female) 
 Race (White/Non-white) 
 Ethnicity (Hispanic or latino/ Not Hispanic or latino) 


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10.
SAFETY EVALUATION
10.1. 
Overview of Safety Analysis Methods 
All safety analyses will be completed for the Safety Population. All safety data will be tabulated 
and listed. No formal statistics or imputation will be performed for the safety analysis. Safety 
and tolerability will be assessed by: 
    Incidence of AEs and SAEs throughout the entire duration of the study 
 Incidence of AEs associated with abuse liability using the MADDERS®  
 Assessment of physical examination findings 
 Changes from baseline (Visit 2) in ECG results 
 Changes from baseline (Visit 2) in clinical laboratory test results 
 Changes from baseline (Visit 2) in vital signs and weight 
 Indications of increased suicidal ideation or behavior as assessed by the C-SSRS 
 Changes from baseline (Visit 2) in patient-rated CSFQ-14 in males and in females, 
assessed separately 
 Change from baseline Visit 5 or End of Treatment) in the SOWS at the safety 
follow-up visit 
10.2. 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation patient administered an IP that does not necessarily 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 related to the medicinal product, or not. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. Worsening of a 
pre-existing condition is considered an AE. 
Events that occur in patients treated with placebo, or during treatment free periods of the study, 
are also considered AEs.  
An AE is defined as treatment-emergent if the first onset or worsening is during or after the first 
administration of IP. AEs (serious and non-serious) that are ongoing at the last study visit should 
be followed for up to 28 days following the last dose or until one of the above conditions 
(resolution, etc.) is (are) met. In the case of missing or partial dates, an adverse event will be 
considered treatment-emergent unless the available data excludes that possibility. 
An AE summary table will present totals for the following: 
 All treatment-emergent adverse events (TEAEs) 


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 TEAEs by severity (mild, moderate, severe) 
 TEAEs leading to study drug discontinuation  
 TEAEs by relationship (not related, unlikely related, possibly related) 
 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 patient will be counted only once within each summation level (SOC; preferred term).  If a 
patient experiences more than one TEAE within each summation level, the TEAE with the 
strongest relationship or the maximum severity, as appropriate, will be included in the 
summaries of relationship and severity. 
All AEs will be presented in a listing. 
These summaries will include SAEs; additionally, they will be presented separately (see below). 
10.3. 
Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
Summaries of incidence rates (frequencies and percentages) of individual SAEs by MedDRA 
SOC and preferred term will be presented.  Additionally, SAEs will be listed separately. 
TEAEs leading to discontinuation of study drug will be analyzed and presented in a manner 
identical to the SAEs. 
Adverse events potentially related to abuse identified via the Misuse, Abuse, Diversion Drug 
Event Reporting System (MADDERS®) will be presented in a separate listing. 
All deaths will be reported in a listing.  
10.4. 
Clinical Laboratory Evaluation 
Laboratory data including Chemistry, Hematology, and urinalyses 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 for each clinical laboratory analyte and for 
each treatment group.  95% confidence intervals will be presented for change from baseline. 
Laboratory values will be displayed in the data listings with their corresponding normal ranges, 
and those values that are outside the normal range will be flagged 
Results of urine drug screens and pregnancy tests will be presented in listings. 
  


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10.5.
Vital Signs, ECGs, Physical Findings, and Other Observations 
Related to Safety 
10.5.1. 
Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline at each assessment time point will be reported for vital signs including 
weight, body mass index, body temperature, pulse rate, systolic blood pressure and diastolic 
blood pressure. 95% confidence intervals will be presented for change from baseline. Vital sign 
values, including abnormal values, will be listed. 
10.5.2. 
ECGs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline at each assessment time point will be reported for each ECG parameter. 
95% confidence intervals will be presented for change from baseline. 
The ECG interpretation will be performed by the central reader and confirmed by the 
Investigator, recorded in the CRF as normal, abnormal but not clinically significant, or abnormal 
and clinically significant.  The number and percentage of patients in each category will be 
reported in shift tables vs the baseline interpretation at each visit. 
ECG values, including interpretation, will be listed. 
10.5.3. 
Physical Examinations 
Physical examination data will be presented in a data listing 
10.5.4. 
Other Safety Measures 
10.5.4.1. Columbia Suicide Severity Rating Scale (C-SSRS) 
Based on the C-SSRS results, the overall number of patients with lifetime and/or current suicidal 
ideation (by item and category), suicidal behavior (by item and category), or self-injurious 
behavior at the screening and baseline visit will be summarized by visit and treatment group.  
Additionally, the overall number of patients with any suicidal ideation or behavior (by type and 
in total) or self-injurious behavior while on-treatment will be provided by treatment group. 
Patients will only be counted once for on-treatment ideation and on-treatment behavior, at the 
worst-case response for each item. 
10.5.4.2. Changes from baseline in the Sexual Functioning Questionnaire Short-Form 
(CSFQ-14) 
The CSFQ-14 will be analyzed by gender. Note: there is a male version and female version for 
the CSFQ-14. 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 each CSFQ domain score and the total. Note that the CSFQ is considered 
both an efficacy and safety endpoint. 


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10.5.4.3. Subjective Opiate Withdrawal Scale (SOWS) 
The SOWS is a self-administered 16-item scale for evaluating opioid withdrawal symptoms. The 
SOWS will be administered at End of Treatment (Visit 5/ET) (after 6 weeks of treatment/ET), 
then completed at home at +1 day, +2 days, +3 days, +6 days, +9 days, and +12 after Visit 5/ET, 
and lastly administered at the Post Study Follow-up (Visit 6).  Operationally, the timing of 
assessments are anchored around the last dose as entered into the EDC; in the case of entry errors 
of this field, assessments may be triggered on days differing from the above schedule.  In these 
instances, the date of last dose will be used as anchor and available assessments will be 
windowed as follows: 
Day 
Window 
End of Treatment 
Last assessment on/ prior to last dose day, with priority given to the 
in-clinic assessment 
Day +1 
Day +1 from last dose 
Day +2 
Day +2 from last dose 
Day +3 
Day +3, 4 from last dose 
Day +6 
Day +5, 6, 7 from last dose 
Day +9 
Day +8, 9, 10 from last dose 
Day +12 
Day +11 from last dose and later 
Follow-up Visit 
In-clinic assessment at follow-up visit.  This visit may also be utilized 
for one of the above visits if it falls in-window and there are no at-
home assessments in-window. 
If there is more than one assessment in-window with equal priority, then the one closest to the 
planned day will be used.  In the case of ties, the set of questions with the highest total SOWS 
score will be used for tabulations (but all assessments will be listed). 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline (Visit 5/ET) at each assessment time point will be reported for the total 
SOWS score and each individual question. 95% confidence intervals will be presented for 
change from baseline. 
10.5.4.4. Misuse, Abuse, Diversion Drug Event Reporting System (MADDERS®) 
The MADDERS® is a structured method to: 
 Identify potential abuse-related events associated with study drug  
 Classify the events according to standardized definitions 


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 Identify potential abuse-related events not already classified as an adverse event of 
interest or drug accountability discrepancy. 
The Investigator at each site will be trained to identify related adverse events and drug 
accountability discrepancy. This information is collected throughout the study in real time. If any 
of these events are identified during the study, the Investigator will determine if it matches a 
MADDERS® triggering event. If so, the MADDERS® Supplemental Adverse Event Form or the 
MADDERS® Supplemental Drug Accountability Form will be completed. These events are 
adjudicated by a MADDERS® Adjudication Committee after the patient exits the study. 
In addition to, all participants (regardless of the occurrence of a MADDERS® triggering events) 
will complete the MADDERS® Medication Use Survey on Visit 6. If the participant is lost to 
follow-up prior 
knowledge of the participant. 
The MADDERS® events will be reported in a separate appendix to the CSR and is outside the 
scope of this SAP.  
The MADDERS® Medication Use Survey will be summarized by treatment with the count and 
percentage of patients with each response to each question. 
  
 


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11.
OTHER ANALYSES
N/A 
 
 


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12.
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL
 
 
 
 
 
 


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13.
REFERENCES
Diggle P, Kenward M. Informative dropout in longitudinal data analysis (with discussion). Appl 
Stat. 1994;43:49-93 
Lu K. and Mehrotra D.V. Specification of covariance structure in longitudinal data analysis for 
randomized clinical trials. Statistics in Medicine 2010 Feb 20; 29(4):474-88. 
592. 
 
  
 


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14.
APPENDIX
14.1. 
Schedule of Events 
Procedures and Evaluations 
Screening 
Baseline 
Double-Blind Treatment 
Period 
Post Study 
Follow-up 
Visit 
1 
2 
3 
4 
5 or 
ET 
6 
Study Week 
-5 to -1 
0 
2 
4 
6 
8 
Study Day 
-35 to -7 
1 
15 ± 2 
29 ± 2 
43 + 2 
57 + 7 
Screening 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Optional Pharmacogenomics consent
Xg 
 
 
 
 
 
Clinical Trial Subject Registry 
Consent 
Xk 
 
 
 
 
 
Placebo response traininga 
X 
X 
X 
X 
X 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Psychiatric history (MINI 7.0.2) 
X 
 
 
 
 
 
MSI-BPD 
X 
 
 
 
 
 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X  
Demographics and medical history 
X 
 
 
 
Xl 
 
Vital signs, weight, heightb, and 
BMI 
X 
X 
X 
X 
X 
X 
Physical examination, including a 
brief neurological exam 
X 
 
 
 
X 
 
12-lead ECG 
X 
X 
 
 
X 
 
Pregnancy testc  
X 
X 
X 
X 
X 
X 
Urine drug screend 
X 
 
 
 
 
 
Clinical laboratory assessments 
X 
 
 
X 
X 
 
PK  
 
 
 
X 
X 
 
Randomization 
 
X 
 
 
 
 
Study Drug 
 
 
 
 
 
 
Dispense study drug 
 
Xf
X
X
 
Study drug return, compliance, and 
accountability
 
 
X 
X 
X 
 
Optional Pharmacogenomics 
 
 
 
Blood sample collection 
 
Xg 
* 
* 
* 
* 
Efficacy 
 
 
 
MADRS
X 
X
X
X
X
CGI-S
 
X
X
X
X
CGI-I 
 
 
X
X
X
HARS 
 
X 
X 
X 
X 
 
SDS 
 
X
X
X
X
PGIC 
 
 
X 
X 
X 
 
PGIS 
 
X
X
X
X
Safety 
 
 
 
AEs
 
X
X
X
X
X
MADDERS®
 
 
Xh 
Xh 
Xh 
Xi
C-SSRS 
X 
X 
X 
X 
X 
X 
CSFQ-14 
 
X
X
SOWS
 
 
X
Xj
Abbreviations: AE = adverse event; ET = early termination; BMI = Body Mass Index; TSH=Thyroid Stimulating Hormone; CGI-I = Clinical 
Global Impression  Improvement scale; CGI-S = Clinical Global Impression  Severity scale; HARS = Hamilton Anxiety Rating Scale; CSFQ-
14 = Changes in Sexual Functioning Questionnaire Short-Form; C-SSRS = Columbia-Suicide Severity Rating Scales; ECG = Electrocardiogram; 
MADRS = Montgomery-Åsberg Depression Rating Scale; MINI 7.0.2 = Mini International Neuropsychiatric Interview, Version 7.0.2; MSI-BPD 
= McLean Screening Instrument for Borderline Personality Disorder; PGIC = Patient Global Impression of Change; PGIS = Patient Global 


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Impression of Severity; PK = pharmacokinetic; SDS = Sheehan Disability Scale; MADDERS® = Misuse, Abuse, Diversion Drug Event 
Reporting System; SOWS = Subjective Opiate Withdrawal Scale. 
a 
A placebo response reduction document is presented to patients by study staff for review and discussion at every in-clinic visit from 
Screening (Visit 1)  through end-of Treatment (Visit 5/ET). 
b 
Height to be measured at Screening (Visit 1)  only. 
c 
Serum pregnancy test at Screening (Visit 1)  and on-site urine pregnancy test at all other visits for all women of childbearing potential, 
including women who have had bilateral tubal ligation. Serum pr
 End of 
Treatment (Visit 5/ET). 
d 
Performed at Screening (Visit 1) and only at other visits if Investigator suspects drug use or if a prescribed scheduled medication is washed 
out to participate in the study (eg., benzodiazepines, stimulants, opioids). At Screening, both an on-site urine dip-stick and a central laboratory 
sample will be obtained.  
e 
Chemistry, Hematology, HbA1c and TSH at Screening. Chemistry and Hematology only at Visit 4 and Visit5. 
f 
Patient will take first dose of study drug at the clinic at the end of Baseline (Visit 2). 
g 
PGx sample ideally taken at Visit 2 but can be taken at any post-Baseline visit as well (*), noting that Baseline (Visit 2) is best due to 
potential for discontinuation before subsequent visits. 
 
h 
MADDERS® questionnaires will be administered only if any pre-defined AEs and/or DADEs suspect for misuse, abuse or diversion event is 
identified, or any drug accountability issues above the pre-defined threshold are identified. 
i 
MADDERS® Medication Use Survey will be administered to all patients at Visit 6. 
j 
To be completed at +1 day, +2 days, +3 days, +6 days, +9 days, and +12 days at home after the Completion of Treatment, and then in-
person at the Post Study Follow-up visit. 
k  
The Clinical Trial Subject Registry (CTSR) is a mandatory part of the consent process. A site can elect not to participate in the CTSR, with 
approval from the sponsor, and there will be no protocol deviations recorded for leaving it out of the procedures.   
l 
Collection of demographics at Visit 5/ET will only include re-collecting current nicotine, alcohol, and THC usage patterns post double-
blind treatment.  
 
14.2. 
Random Seeds 
The following list of numbers will be used for random seeds where required for MI processes: 
54748395 
35852537 
55264123 
85945257 
84116945 
34285262 
13458178 
72845657 
28932945 
95785785 
These will generally be used in order for the primary analysis, then secondary endpoints and 
sensitivity analyses.  For cases where identical code may be applied to more than one outcome or 
a sensitivity analysis that uses a minor variation on the primary code, the second to last digit will 
be incremented by 1 to produce new seeds for the subsequent outcome/analysis.  If a single 
dataset requires more than the 10 seeds above, additional seeds will be generated by 
incrementing the last digit by 1.  All seeds used will be documented in the programming 
specifications and the programs themselves. 


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15.
ATTACHMENTS
N/A