Clinical trial NCT05472090
Conditions: Post-Acute Sequelae of SARS-CoV-2 (PASC) Infection COVID-19 Long COVID Long Haul COVID
Keywords: Multi-site pain Sleep disturbance PASC COVID-19 Long COVID Coronavirus infections
Sponsor: Tonix Pharmaceuticals, Inc.
Start date: 2022-08-18; Completion date: 2023-07-27
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, randomized, parallel-group, double-blind, placebo-controlled, 14-week study designed to evaluate the efficacy and safety of TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) taken once daily at bedtime for the management of multi-site pain associated with Long COVID.

Detailed description:

Arms: arm 1: 1 x TNX-102 SL 2.8 mg Tablet taken sublingually each day at bedtime for 2 weeks, then 2 x TNX-102 SL 2.8 mg (5.6 mg) Tablet taken sublingually each day at bedtime for 12 weeks. arm 2: 1 x Placebo Tablet taken sublingually each day at bedtime for 2 weeks, then 2 x Placebo Tablet taken sublingually each day at bedtime for 12 weeks.
Interventions: intervention 1: TNX-102 SL intervention 2: Placebo SL Tablet
Intervention descriptions: intervention 1: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks. intervention 2: Patients will take 1 tablet of randomly assigned study drug sublingually starting on Day 1 for 2 weeks. At the Week 2 visit, all patients will have the dose increased to 2 tablets for 12 weeks.

Protocol documents:
Prot_000.pdf: 
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TNX-102 SL (CYCLOBENZAPRINE HCL SUBLINGUAL TABLETS) 
 
TNX-CY-PA201 
 
A PHASE 2, 14-WEEK DOUBLE-BLIND, RANDOMIZED, 
MULTICENTER, PLACEBO-CONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
TNX-102 SL TAKEN DAILY AT BEDTIME IN PATIENTS 
WITH MULTI-SITE PAIN ASSOCIATED WITH 
POST-ACUTE SEQUELAE OF SARS-COV-2 INFECTION 
(PASC)  
“THE PREVAIL STUDY” 
 
Protocol Amendment 2 Release Date: 13 Oct 2022 
Replaces Protocol Amendment 1 Release Date: 29 Apr 2022 
Original Protocol Release Date: 24 Nov 2021 
US IND No. 156272 
 
Sponsor: 
Tonix Pharmaceuticals, Inc. (Tonix) 
 
 
 
For Tonix: 
 
 
 
                           
 
 
 
 
 Confidentiality Statement: The information herein contains trade secrets and commercial information that are 
privileged or confidential and the proprietary property of Tonix Pharmaceuticals. Any unauthorized use or 
disclosure of such information without the prior written authorization of Tonix is expressly prohibited. No part of 
this document may be reproduced or transmitted in any form without written permission from Tonix, except as 
required by federal or state laws. Persons to whom this information is disclosed by written consent must be informed 
that all the information herein is privileged and confidential and may not be further divulged. These restrictions on 
disclosure will apply equally to all future information supplied to you that is indicated to be privileged or confidential. 




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INVESTIGATOR’S AGREEMENT 
 
I have read the TNX-CY-PA201 protocol and agree to conduct the study as outlined. I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.  
 
 
 
 
 


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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Tonix Pharmaceuticals, Inc. 
Name of Investigational Product: 
TNX-102 SL (Cyclobenzaprine HCl Sublingual Tablets) 
Name of Active Ingredient: 
Cyclobenzaprine HCl 
Title of Study:  
A Phase 2, 14-week Double-Blind, Randomized, Multicenter, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of TNX-102 SL Taken Daily at Bedtime in Patients with 
Multi-site Pain Associated with Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) 
(Protocol No. TNX-CY-PA201) 
Study center(s): Approximately 30 centers in the United States 
Estimated Studied period: 16 months 
Estimated date first patient enrolled: August 2022 
Estimated date last patient completed:  November 2023 
Phase of development: 2 
Objectives:  
Primary 
To evaluate the efficacy of TNX-102 SL 5.6 mg daily at bedtime in the treatment of patients with 
multi-site pain associated with Long COVID. 
Secondary 
To evaluate the safety and tolerability of TNX-102 SL 5.6 mg daily at bedtime in the treatment of 
multi-site pain associated with Long COVID.  
 
Methodology:  
This is a Phase 2, randomized, parallel-group, double-blind, placebo-controlled, 14-week study 
designed to evaluate the efficacy and safety of TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) taken 
once daily at bedtime for the management of multi-site pain associated with Long COVID. The 
study is to be conducted at approximately 30 investigational sites in the United States.  
The study will consist of a Screening Visit (Visit 1, Days -35 to -7), a Washout and Screening 
period of at least 7 days (for those patients not requiring washout) and no more than 35 days, 
inclusive of a 7-day baseline data collection phase immediately preceding the Baseline Visit. 
Eligible patients who provide written informed consent will have study assessments performed at 
Screening. Due to limitations in the diary completion window, patients who are planning on 


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international travel during the study period should not be considered for the study. Patients 
whose employment involves overnight shifts also should not be considered for the study due to 
the restricted completion window and the requirement for consistent bedtime dosing. 
At Screening Visit 1 and after signing the written informed consent, any required washout should 
be discussed with the patient and plans made for an appropriate schedule for reducing/stopping 
any excluded medications. This down-titration and discontinuation of excluded medications must 
be accomplished so that the patient is free of excluded medications at least 14 days prior to 
beginning of the collection of Baseline diary data that takes place during the 7 days leading up to 
the Baseline/Randomization Visit. Any additional time required for down-titration would be in 
addition to this washout requirement. For extenuating circumstances, the total duration of the 
Screening period may be increased to up to a maximum of 49 days with Medical Monitor 
approval. All excluded medications will be stopped during the Washout period through 
Week 14/Early Termination Visit (ET) (Visit 6).  
Pre-randomization Approval by Tonix Pharmaceuticals will be required prior to the 
Baseline/Randomization Visit (Visit 2) in addition to satisfying all other eligibility and 
randomization criteria. 
The Screening period will be followed by the Baseline/Randomization Visit (Visit 2, Day 1), and 
4 in-clinic visits at Weeks 2, 6, 10, and 14/ET. Due to the exceptional circumstances caused by 
the COVID-19 pandemic, an option for a telephone visit will be available for Weeks 2, 6, 10 
(Visits 3, 4, 5), and, only with Medical Monitor approval, Week 14/Visit 6 (or ET) for those 
unable to attend an in-clinic visit due to the COVID-19 pandemic. Approximately 2 weeks after 
Week 14 (Visit 6), there will be an initial Post-study Safety Follow-up telephone call (Visit 7), 
and approximately 4 weeks after Week 14, there will be a 1-Month Safety Follow-up telephone 
call (Visit 8). The total duration for each individual participant in the study, including Screening, 
may be as long as 25 weeks. The maximum treatment duration will be 14 weeks. 
Patients will be trained on use of the electronic diary (eDiary) system at Visit 1. During the 7-day 
run-in Phase (7 days immediately preceding Visit 2 [Baseline/Randomization Visit; Day 1]) 
patients will be asked to record their worst daily Long COVID pain intensity on the 11-point 
(0−10) numeric rating scale (NRS) scale using 24-hour recall and assess sleep quality from the 
previous evening, also using an 11-point NRS scale. The average of the 7 days immediately 
preceding Visit 2 (Baseline Randomization Visit; Day 1) will serve as the Baseline pre-treatment 
scores.  
After completing any required washout of excluded therapies and recording Baseline Diary 
scores for at least 7 days, patients will return to the investigative site for Baseline assessments 
and randomization (Day 1, Visit 2), when they will be randomly assigned to receive 
TNX-102 SL or matching placebo sublingual tablet in a 1:1 ratio.  
Patients will take the study drug sublingually (SL) once daily at bedtime, starting on the day of 
randomization (Day 1), for 14 weeks. For the first 2 weeks of treatment, patients will start on 
TNX-102 SL 2.8 mg/day (1 tablet) or placebo.  
All patients will then return to the clinic at Week 2 (Visit 3) for efficacy and safety assessments 
and assessment of study drug compliance. The study drug dose will be increased to 2 tablets 
(5.6 mg; 2 x 2.8 mg of TNX-102 SL or placebo) taken sublingually and simultaneously daily at 


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bedtime. Patients will next return to the clinic at Week 6 (Visit 4) for assessment of safety, 
efficacy, study drug compliance, and dose tolerability at the 5.6-mg daily dose. In scenarios in 
which TNX-102 SL 5.6 mg (or 2 placebo tablets) is considered intolerable due to adverse 
event(s) (AEs) and would otherwise lead to study discontinuation, with Medical Monitor 
approval, the Investigator may lower the dose back to 1 tablet every night (TNX-102 SL 2.8 mg 
or 1 placebo tablet). If/when it is deemed clinically warranted by the Investigator, re-challenge 
with 2 tablets TNX-102 SL 2.8 mg (5.6 mg dose)/placebo may be attempted, or the patient may 
remain on the lower dose for the remainder of the study. Patients will return to the clinic for 
safety, tolerability, and efficacy assessments, and assessments of study drug compliance at 
Weeks 10 (Visit 5) and 14 (Visit 6) or ET and will receive two safety follow-up calls 
approximately 2 weeks (Visit 7) and 4 weeks (Visit 8) later.  
During the treatment phase, each evening, the eDiary will prompt the patient to reflect on the past 
24 hours and record their worst pain intensity, assess their sleep quality from the previous 
evening, and log study drug dosing from the previous night (post-randomization). 
Patients who wish to withdraw from the study may do so at any time. 
Number of Patients (planned):  
Approximately 470 patients (235 per arm) will be randomized in a 1:1 ratio to treatment with 
TNX-102 SL or placebo tablets. Randomized patients who withdraw will not be replaced. 
Diagnosis and main criteria for inclusion:  
 
Inclusion criteria (assessed at screening [Visit 1]): 
 
1. The patient is male or female, 18 to 65 years of age, inclusive. 
2. The patient has a confirmed history of SARS-CoV-2 infection at least 3 months prior to 
enrollment, based on a documented written positive viral test at the time of active 
infection through either a polymerase chain reaction (PCR) or nucleic acid tests or a rapid 
antigen test. Acceptable documentation of SARS-CoV-2 infection may be through either 
a laboratory report or formal documentation either generated at the point-of-care or by a 
virtual at-home test proctor/telehealth service. 
3. The patient has a history of COVID-19 infection with a grading of 1 to 6 on the World 
Health Organization (WHO) COVID-19 8-Category Ordinal Scale of Disease Severity 
(Appendix 1). 
4. The patient has new onset or significant worsening of pain that coincides with a prior 
COVID-19 infection. The new or worsening pain following COVID-19 infection has 
been generally present for at least 3 months post initial COVID-19 diagnosis, but no 
longer than 18 months post initial COVID-19 diagnosis. 
5. The patient meets criteria for multi-site pain as defined by the modified Michigan Body 
Map (mMBM) closely following the SARS-CoV-2 infection, which includes: 
• Multi-site pain, characterized as pain in at least 4 out of 7 body regions (mMBM 
Part 2, Appendix 2) 


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6. The patient’s in-clinic 7-day recall NRS average daily Long COVID pain intensity score 
at Screening Visit must be ≥ 4 and ≤ 9 (Appendix 3). Exceptions are only possible with 
Medical Monitor’s approval. 
7. The patient has a Post-COVID-19 Functional Status Scale (PCFS) score of ≥ 2 
(Appendix 4) at Screening and Baseline. 
8. The patient does not have another disorder that would otherwise explain his/her pain. 
9. 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 28 
days after study drug discontinuation: 
a. Hormonal methods such as oral, implantable, injectable, or transdermal contraceptives 
for a minimum of one full cycle (based on the patient’s usual menstrual cycle period) 
before study drug administration; 
b. Intrauterine device; 
c. Bilateral tubal ligation 
d. Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal 
jelly or cream); 
e. Partners of vasectomized males in stable relationships; 
f. Females involved in same-sex relationships; 
g. Female patients practicing abstinence may have the birth control requirement waived 
only with Medical Monitor approval. 
10. If the patient is vaccinated against the SARS-CoV-2 virus, the patient is at least 2 weeks 
past a vaccine dose.  
11. If the patient is currently receiving any non-exclusionary pharmacologic treatments, the 
patient should be on stable doses of their treatment regimen for at least 4 weeks (except 
for allowed antidepressants, which require 90 days at stable dose) prior to randomization 
and should not be expecting dosing change during the period of the trial. 
12. The patient must be willing and able to withdraw from the following therapies for the 
duration of the study: duloxetine, milnacipran, pregabalin, gabapentin, tramadol, 
tapentadol, amitriptyline and other tricyclic antidepressants, trazodone, narcotics/opioids, 
naltrexone (including CONTRAVE®), all other forms of cyclobenzaprine (AMRIX®, or 
generic equivalents), orexin receptor antagonists, and benzodiazepines. 
13. The patient is willing and able to comply with all protocol-specified requirements. 
14. The patient is capable of reading and understanding English and has provided written 
informed consent to participate.  
 
Exclusion criteria (Assessed at the screening [Visit 1]): 
 
1. The patient has been diagnosed with infectious or inflammatory arthritis (eg, rheumatoid 
arthritis, ankylosing spondylitis, psoriatic arthritis), systemic lupus erythematosus, gout, 
or meets criteria for another type of systemic autoimmune disease (eg, Sjogren’s disease). 
2. The patient has been diagnosed with a complex regional pain syndrome, fibromyalgia, 
failed back surgery syndrome, persistent or prevalent pain symptoms related to systemic 
disease (eg, diabetic peripheral neuropathy, post-herpetic neuropathy), untreated 
hyperparathyroidism, or a history of prior surgery, trauma, organ or tissue damage, or 
other source of pain that, in the Investigator’s opinion, would confound or interfere with 


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the assessment of the patient’s symptoms or require excluded therapies during the 
patient’s study participation. 
3. The patient has any lifetime history of bipolar disorder, schizophrenia, schizoaffective 
disorder, or other psychotic disorder as determined at Screening either by history or by 
the Mini International Neuropsychiatric Interview, Version 7.0.2 (MINI 7.0.2) Module A 
(Major Depressive Episode), Module C (Manic and Hypomanic Episodes), Module K 
(Psychotic Disorders), and Module O (Rule Out Medical, Organic, or Drug Causes for 
All Disorders). 
4. History of or evidence for a diagnosis of borderline personality disorder (BPD) based on 
a score of ≥ 7 on the McLean Screening Instrument for BPD (MSI-BPD) at Visit 1 
(Screening).  
5. The patient is at increased risk of suicide on the basis of the Investigator’s judgment, or 
the results of the Columbia Suicide Severity Rating Scale (C-SSRS) conducted at 
Screening and Baseline (eg, any C-SSRS suicidal behavior or C-SSRS Type 3, 4, or 5 
ideation during the preceding 6 months and any suicidal behavior within the past 
12 months). 
6. The patient has participated in any other study with TNX-102 SL. 
7. The patient has a history of COVID-19 infection with a grading of ≥ 7 on the WHO 
COVID-19 8-Category Ordinal Scale of Disease Severity (Appendix 1). 
8. Based on screening laboratory results, thyroid-stimulating hormone (TSH) > 1.5 times the 
upper limit of normal, aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) > 2 times the upper limit of normal, or glycated hemoglobin (HbA1c) > 7.5%; or, 
in the Investigator’s opinion, evidence of a clinically significant laboratory abnormality 
based on Screening laboratory tests or medical history. 
9. Diagnosed with clinically significant and currently relevant cardiac disease (eg, 
significant arrhythmia; heart block; heart failure; symptomatic coronary artery disease or 
orthostatic hypotension), recent myocardial infarction [within the past 2 years]) or QTcF 
> 450 msec (male) or > 470 msec (female) on the screening electrocardiogram (ECG). 
10. The patient currently has or has a history of a clinically significant systemic viral 
infection (eg, human immunodeficiency virus [HIV], hepatitis B or C). 
11. The patient is currently receiving or is expected to need systemic corticosteroids (> 5 mg 
prednisone or equivalent per day) or has received acute treatment with systemic 
corticosteroids within 28 days of the Baseline Visit, or is likely to require such treatment 
during the study. 
12. The patient has received tender point, trigger point, or other local injections with 
anesthetic agents (or corticosteroids, as per Exclusion Criterion #11) within 28 days of 
the Baseline Visit, or is unable to refrain from such injections during the study. 
13. The patient is unable to successfully washout of the following medications during 
Screening, or washout is inadvisable: monoamine oxidase inhibitors (30-day washout 
required), levomilnacipran, anticonvulsants (aside from those used as migraine 
prophylaxis), amphetamine mixed salts, weight loss agents such as phentermine and 
diethylpropion, muscle relaxants (eg, methocarbamol, baclofen, carisoprodol, 
cyclobenzaprine), stimulants (eg, methylphenidate, lisdexamfetamine, 
dextroamphetamine), mirtazapine, trazodone, nefazodone, St. John’s wort, any 
medication known to be a strong CYP3A4 inhibitor (Appendix 5) or any of the 
medications listed in Inclusion Criterion #12.  


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14. Positive results for illegal or abused substances other than cannabis/THC at Screening or 
Baseline or history of substance use disorder during the preceding 1 year as defined by 
the screening MINI 7.0.2 Module J (Substance Use Disorder). Patients who utilize 
alcohol and/or cannabis/THC but do not meet criteria for greater than MILD Alcohol Use 
Disorder in Module I (Alcohol Use Disorder) and/or MILD Cannabis Use Disorder in 
Module J in the preceding 1 year are suitable for the study provided that, in the judgment 
of the Investigator, this usage will not interfere with the patient’s ability to complete the 
study or provide reliable data. 
15. Use of chewing or dipping tobacco or betel nut in the previous 6 months. 
16. Planned use of teeth-whitening strips or prescription teeth-whitening products over the 
course of study participation. 
17. Any existing oral, medical, or dental condition that could potentially interfere with the 
sublingual administration of study drug, the tolerability of study drug or with the 
evaluation of administration site reactions. 
18. Any history of severe or unexplained oral or oropharyngeal swelling or edema. 
19. The patient has any clinically significant, uncontrolled, or unstable medical or surgical 
condition that could affect his or her ability to participate in the study or potentially 
compromise his or her well-being during the study. Patients with history of malignancy 
within 5 years of screening (other than treated carcinoma in situ of the cervix, basal cell 
carcinoma, or Type 1 squamous cell carcinoma of the skin) must receive Medical Monitor 
approval prior to randomization. 
20. The patient has an anticipated need for surgery that might confound results or interfere 
with his or her ability to comply with the protocol. 
21. The patient is pregnant or nursing. 
22. The patient has a hypersensitivity to cyclobenzaprine or the excipients in TNX-102 SL or 
placebo formulations or any contraindications to the use of cyclobenzaprine (such as 
history of urinary retention or increased intraocular pressure). 
23. The patient has a seizure disorder or neuropathic pain that requires anticonvulsant 
therapy. 
24. 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 continuous positive airway 
pressure or oral device, are allowed at the discretion of the Investigator.  
25. The patient has a BMI > 38.0 kg/m2 (due to the increased risk of sleep apnea). 
26. The patient has a history of narcolepsy, cataplexy, restless leg syndrome, periodic 
involuntary limb movement disorder or other documented, clinically significant sleep 
disorder.  
27. The patient has plans for international travel, or has a work schedule (eg, requiring night 
shifts), that prevents them from being able to utilize the diary system during its available 
time window or to take study medication on a regular basis. 
28. The patient is currently being treated with immunosuppressive medication, sodium 
oxybate, ketamine, esketamine, or calcitonin gene-related peptide (CGRP) receptor 
antagonists. 
29. The patient has received an investigational CGRP receptor antagonist within 90 days of 
Screening, or any other investigational drug within 30 days of Screening. 


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30. The patient is currently receiving other therapies to treat acute COVID-19 symptoms or 
severity, such as convalescent plasma, remdesivir, or dexamethasone 
31. The patient has another active systemic bacterial or fungal infection, or the patient is 
taking medications to treat another type of active infection 
 
Randomization criteria (assessed at Visit 2, Baseline): 
Only those patients meeting all of the following randomization criteria are eligible for 
randomization: 
1. Continues to meet all inclusion and exclusion criteria, including urine and blood test 
results, and is successfully and consistently utilizing the diary system. 
2. Patient’s pain satisfies the following criteria, as assessed by diary pain scores (24-hour 
recall): 
a.  A mean worst daily Long COVID pain intensity score ≥ 4 and ≤ 9 on the 11-point 
(0−10) NRS for the 7 days immediately preceding Visit 2, and 
b.  No more than 2 individual days with a Long COVID pain score < 4 on the 7 days 
immediately preceding Visit 2, and 
c.  No score of 10 on any of the 7 days immediately preceding Visit 2, and  
d.  Long COVID pain scores recorded on at least 5 out of the 7 days immediately 
preceding Visit 2. 
 
Investigational product, dosage and mode of administration: 
Name: TNX-102 SL (cyclobenzaprine HCl sublingual tablets) 
Dose, route, frequency: For Days 1−14, 1 tablet of TNX-102 SL 2.8 mg taken sublingually 
(under the tongue) each day at bedtime. For Days 15−98, 2 tablets of TNX-102 SL 2.8 mg 
(5.6 mg) taken simultaneously and sublingually (under the tongue) each day at bedtime. 
Duration of treatment:  
14 weeks 
Reference therapy, dosage and mode of administration: 
Name: Placebo 
Dose, route, frequency: For Days 1−14, 1 tablet of placebo taken sublingually (under the tongue) 
each day at bedtime. For Days 15−98, 2 tablets of placebo taken simultaneously and sublingually 
each day at bedtime. 
 
Treatment Regimens: 
Patients will take 1 tablet of randomly assigned study drug sublingually at bedtime once daily 
starting on Day 1 for 2 weeks; then patients will take 2 tablets of assigned study drug 
simultaneously and sublingually once daily starting on Day 15 for 12 weeks. A drink of water is 
recommended prior to dosing for patients with a dry mouth. Patients will be asked to keep the 


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tablet(s) under the tongue until dissolved (approximately 90 seconds) and not to crush or chew 
the tablets. Patients should not eat, drink, or chew gum for at least 15 minutes after dosing, and 
preferably not to drink any hot, cold, or acidic beverage until morning. Patients should also 
refrain from talking for at least 5 minutes after dosing.  
In scenarios in which the daily dose of 2 tablets (5.6 mg) is considered intolerable and would 
otherwise lead to study discontinuation, with Medical Monitor approval, the Investigator may 
lower the dose to 1 tablet (2.8 mg) per day. If/when it is deemed clinically warranted by the 
Investigator, re-challenge with 2 tablets TNX-102 SL 2.8 mg (5.6 mg dose)/placebo may be 
attempted.  
Criteria for Evaluation: 
Efficacy: 
Primary efficacy endpoint: 
• Change from Baseline in the diary NRS weekly average of daily self-reported worst Long 
COVID pain intensity scores at the Week 14 endpoint. 
Key secondary efficacy endpoints:  
• Change from Baseline in the weekly average of the daily diary NRS assessment of sleep 
quality at the Week 14 endpoint  
• Change from Baseline in the PROMIS score for fatigue at the Week 14 endpoint 
• Change from Baseline in the PROMIS score for cognitive function at the Week 14 
endpoint 
Secondary efficacy endpoints: 
• Change from Baseline in the Patient Reported Outcomes Measurement Information 
System (PROMIS) score for sleep disturbance at the Week 14 endpoint  
• Proportion of patients with a Patient Global Impression of Change (PGI-C) rating of 
“very much improved” or “much improved” at the Week 14 endpoint 
• Change from Baseline to Week 14 in the Sheehan Disability Scale (SDS) 
• Change from Baseline to Week 14 in the Insomnia Severity Index (ISI) 
• Change from Baseline to Week 14 in the Epworth Sleepiness Scale (ESS) 
Exploratory efficacy endpoints: 
• Proportion of patients with a ≥ 30% improvement from Baseline to Weeks 1−14 in the 
daily self-reported worst Long COVID pain intensity score 
• Proportion of patients with a ≥ 50% improvement from Baseline to Weeks 1−14 in the 
daily self-reported worst Long COVID pain intensity scores 
• Proportion of Patients with a PGI-C rating of “very much improved” or “much improved” 
at each post-randomization clinic visit 
• PGI-C (1-7) rating at each post-randomization clinic visit 


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• Change from Baseline in the PROMIS score for sleep disturbance at each post-
randomization clinic visits 
• Change from Baseline in the PROMIS score for fatigue at each post-randomization clinic 
visits 
• Change from Baseline in the PROMIS fatigue symptom questions 1,3,4 (individually and 
summed) at each post-randomization clinic visit 
• Change from Baseline in the PROMIS fatigue impact questions 6,7,8 (individually and 
summed) at each post-randomization clinic visit 
• Change from Baseline in the PROMIS score for cognitive function at each post-
randomization clinic visits 
• Change from Baseline in the weekly average of the daily diary assessment of sleep 
quality at Weeks 1−14 
• Change from Baseline in the weekly average of the daily diary assessment of worst pain 
intensity scores at Weeks 1−14 
• Change from Baseline in laboratory markers of inflammation 
• Change from Baseline to Week 14 in the PCFS 
• Change from Baseline in the total number of modified Michigan Body Map pain regions 
identified as having pain at each post-randomization clinic visit 
• Change from Baseline in average NRS Long COVID pain intensity across the 7 pain 
regions in the modified Michigan Body Map at each post-randomization visit; regions 
without pain identified will be assigned a value of 0 
• Change from Baseline in average NRS Long COVID pain intensity within the index site 
region on the modified Michigan Body Map at each post-randomization visit 
• Change from Baseline in average NRS Long COVID pain intensity within the worst 
region for a given visit on the modified Michigan Body Map at each post-randomization 
visit; this will compare the value for the worst region at a visit and the worst region at 
baseline 
• Subgroup analyses of the above endpoints by severity of their SARS-CoV-2 infection 
using groupings of the WHO ordinal scale of COVID severity as data allow 
• Subgroup analyses of the above endpoints by COVID vaccine status    
 
Safety: 
• Incidence of AEs 
• Changes from Baseline in clinical laboratory tests 
• Changes from Baseline in vital signs 
• Assessment of physical examination findings, including examination of the oral cavity 
• Monitoring suicidality using Columbia Suicide Severity Rating Scale (C-SSRS) 
Prior and Concomitant Medications: 
Patients who are taking certain medications are eligible for the study if they are willing and able, 
and it is medically reasonable, for them to be withdrawn from these medications prior to 


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randomization and then refrain from usage during this study. The specific medications that must 
be withdrawn include duloxetine, milnacipran, pregabalin, gabapentin and other forms of 
anticonvulsants, tramadol, tapentadol, amitriptyline and other tricyclic antidepressants, 
trazodone, narcotics/opioids, naltrexone (including CONTRAVE®), all other forms of 
cyclobenzaprine (AMRIX®, or generic equivalents), orexin receptor antagonists, and 
benzodiazepines.  
Therapies used to treat acute COVID-19 symptoms or severity, such as convalescent plasma, 
remdesivir, or dexamethasone will be prohibited. Due to the exclusion of all opioids (including 
tramadol and tapentadol) during the treatment phase of the study, patients requiring opioids on a 
regular or frequent basis for any indication should not be considered.  
In addition, patients who are taking gabapentin, pregabalin, or any other anticonvulsant due to 
neuropathic pain should not be considered. 
Other prescription or over-the-counter medication not specifically excluded by entry criteria may 
be continued during the study, provided that the patient has been on this medication a stable dose 
for at least 4 weeks (except for allowed antidepressants, which require 90 days at stable dose) 
prior to randomization and is not expecting to change dosages during the period of the study 
In addition, certain other medications will also be prohibited and may require washout or 
exclusion of the patient if washout is not appropriate (eg, trazodone, mirtazapine, 
levomilnacipran, nefazodone, benzodiazepines, non-benzodiazepine sleep aids, stimulants, 
sodium oxybate, ketamine, esketamine, etc.).  
Patients using teeth-whitening products such as whitening strips or prescription whitening 
products must agree to discontinue their use from the day of randomization until the end of their 
study participation.  
After randomization, sedating antihistamines (eg, diphenhydramine, hydroxyzine) can be used as 
needed for insomnia; however, patients must be able to discontinue them during the Screening 
phase and must refrain from their use during the week of baseline data collection preceding 
Visit 2. The use of sedating anti-histamines after randomization should be under the direction of 
the Investigator, and such use should be minimized to no more than a few nights in a 
row, followed by attempts to refrain from use.    
The use of non-prescription nutraceuticals such as melatonin, ramelteon, and valerian root is not 
restricted.   
New medications that are deemed required, in the opinion of the Principal Investigator or another 
physician, will be allowed, including medications needed to treat AEs. If there is a requirement 
for acute opioids, corticosteroids, or other treatments that could confound the evaluation of pain 
throughout the treatment period, the Investigator may consult with the Medical Monitor to 
potentially delay the study visit until the medication is no longer needed. At a minimum, no 
opioid/narcotic should have been utilized within 2 days of a study visit, and ideally there will 
have been no usage during the 7 days prior to any visit, since important efficacy data will be 
collected on the eDiary. 
Rescue medications used by patients throughout the study will be identified and documented 
during study visits. 


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Statistical methods: 
Populations for Analysis:  
 In the case that the study goes to full enrollment or has a sample size increase, the following 
analysis populations are planned for this study: 
• All patients: Used for summaries of dispositions of patients; tabulations of dispositions 
may also use the populations below. 
• Safety population: all patients who receive at least one dose of the investigational 
product. All safety analyses will be performed using this population, analyzed as treated. 
• Intention-to-treat (ITT) population: all patients who are randomized. This is the primary 
population for efficacy analyses, and patients will be analyzed based on their randomized 
treatment. 
In the case of an early stop for efficacy or futility from the interim analysis, the following 
populations will be utilized: 
• All Patients: used for summaries of dispositions of patients; tabulations of dispositions 
may also use the populations below. 
• Interim Safety population: all patients who receive at least one dose of the investigational 
product and included in the cohort of interim analysis patients. All safety analyses will be 
performed using this population, analyzed as treated. 
• Interim ITT population: all patients who are randomized and included in the cohort of 
interim analysis patients. This is the primary population for efficacy analyses, and 
patients will be analyzed based on their randomized treatment. 
• Full Safety population: all patients who receive at least one dose of the investigational 
product. This will be used for supportive safety analyses on all patients exposed in the 
study, analyzed as treated. 
 
Efficacy Analyses: 
The primary efficacy parameter will be the difference between TNX-102 SL and placebo in the 
weekly mean change in worst pain score from Baseline to the Week 14. The weekly pain score 
will be based on the weekly average of the daily diary patient self-reported 24-hour recall worst 
Long COVID pain intensity scores using an 11-point (0−10) NRS. A weekly value will be 
calculated as long as at least one daily measure is recorded.  
The primary ITT analysis will provide the following causal estimand for the primary analysis: 
the difference in the weekly mean change from Baseline of the daily patient self-reported 24-hour 
recall worst Long COVID pain intensity rating using an 11-point (0−10) NRS evaluated at the 
Week 14 endpoint in all randomized patients attributable to the initially randomized treatment 
assignment. The primary analysis will use a Mixed Model Repeated Measures (MMRM) 
approach with multiple imputation (MI) for missing data. Covariates in the model will include 
the fixed categorical effects of treatment, pooled site (with small sites pooled into a single large 
site), study week, and treatment by study week interaction, as well as the continuous fixed 


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prohibited.  
covariates of baseline score and baseline score by study week interaction. Please see the 
separate Statistical Analysis Plan (SAP) for more details on the primary and secondary analyses 
and handling of missing data.   
A hierarchical testing strategy will be applied to perform confirmatory analysis of the primary 
endpoint and key secondary efficacy endpoints; testing will begin with the first endpoint 
(primary endpoint) and continue through the sequence of key secondary endpoints only until an 
endpoint is not statistically significant. The order will be specified in the statistical analysis plan. 
 
Safety Analyses: 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will 
be summarized overall and by preferred term and system organ class. AEs will also be 
summarized by severity and relationship to study drug. Serious AEs, AEs involving the oral 
cavity, and AEs leading to discontinuation of study drug will also be summarized. Actual values 
and changes from Baseline for clinical laboratory test results and vital signs will be summarized 
using descriptive statistics (n, mean, standard deviation, median, range, minimum, and 
maximum). The number of patients with Baseline and treatment-emergent suicidal ideation 
and/or suicidal behavior or self-injurious behavior, based on the C-SSRS, will be summarized by 
treatment group. 
 
Sample Size: 
The study is planned to enroll approximately 470 patients total in a 1:1 randomization; that is, 
235 patients in each of the TNX-102 SL and placebo arms. Using a two-sided test with an alpha 
level of 0.05, a sample size of 235 per group provides a power of at least 90% if the effect size is 
0.3.  
 
Interim Analysis 
An interim analysis will be completed when approximately 50% of the initially planned 
enrollment is evaluable for efficacy assessments. The analysis will be conducted for the purpose 
of potential sample size re-estimation, early stop for futility, and early stop for efficacy. This will 
be evaluated by an independent data monitoring committee; only recommendations on early 
stopping, continuing with the sample size as planned, or a sample size adjustment will be 
communicated to the Sponsor.  
In the case of an early stop for efficacy, all ongoing patients will be asked to return to the clinic 
and complete an ET Visit, and the study will be halted once all patients have completed their 
termination visit. 
Full details of the interim analysis will be included in the SAP and finalized prior to execution of 
the interim analysis. 
 
Pharmacogenomic Analysis 
Potential genetic determinants of treatment response will be examined by the assessment of 
genetic variants in relation to treatment outcome. Blood samples will be obtained from each 


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patient who provided separate written, signed informed consent form for pharmacogenomic 
analysis. These samples may be obtained at any post-screening visit, including an ET Visit; 
however, it is preferred that they are collected at Visit 2 whenever possible.  
The pharmacogenomic analyses will involve whole genome sequencing (WGS) and analysis for 
allelic polymorphisms related to treatment response to TNX-102 SL. 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-102 SL.  
 
 


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Table 2: 
Study Design and Schedule of Assessments 
Assessment 
Screening 
and Washout 
Period a 
Diary 
Run-in 
Period 
Baseline/ 
Randomization 
Week 2 u 
Week 6 u 
Week 10 u 
Week 14 / 
ET b 
Week 16/ 
(Post-study 
Safety 
Follow-up) v 
Week 18/ 
(1-Month Post-
study Safety 
Follow-up) w 
Study Day 
-35 to -1 
-7 to -1 
1 
15 (-4 /+7)  
43 ± 7  
71 ± 7  
99 (-4 
/+7)  
113 ± 7 
127 ± 7 
Visit Number 
V1 
 
V2 
V3 
V4 
V5 
V6  
V7 
V8 
Informed consent 
X 
 
 
 
 
 
 
 
 
In-/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
X c 
 
 
 
 
 
 
Confirmation of prior SARS-
CoV-2 infection x 
X 
 
 
 
 
 
 
 
 
WHO COVID-19 severity 
classification 
X 
 
 
 
 
 
 
 
 
Prior/Concomitant 
medications 
X 
 
X c 
X 
X 
X 
X 
X 
X 
Physical examination 
X d 
 
X e 
 
 
 
X e 
 
 
Inspection of oral cavity f 
X 
 
X 
X 
X 
X 
X 
 
 
Modified Michigan Body 
Map (mMBM) 
X g 
 
X h 
X h 
X h 
X h 
X h 
 
 
MINI 7.0.2 Modules A, C, I, 
J, K, O (MDE, Bipolar, 
EtOH, Substance Use, 
Psychotic Disorders, 
Med/Organic/Drug-Related 
R/Os) 
X 
 
 
 
 
 
 
 
 
MSI-BPD 
X 
 
 
 
 
 
 
 
 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
X 
 
X 
X 
X 
X 
X 
 
 
Sheehan Disability Scale i 
 
 
X 
X 
X 
X 
X 
 
 
In-clinic assessment of Long 
COVID pain (7-day recall) 
X j 
 
 
 
 
 
 
 
 
PROMIS – Sleep 
Disturbance i 
 
 
X 
X 
X 
X 
X 
 
 
PROMIS – Fatigue i 
 
 
X 
X 
X 
X 
X 
 
 
PROMIS – Cognitive 
Function – Abilities i 
 
 
X 
X 
X 
X 
X 
 
 
Patients’ Global Impression 
of Change (PGI-C) 
Assessment i 
 
 
 
X 
X 
X 
X 
 
 


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Assessment 
Screening 
and Washout 
Period a 
Diary 
Run-in 
Period 
Baseline/ 
Randomization 
Week 2 u 
Week 6 u 
Week 10 u 
Week 14 / 
ET b 
Week 16/ 
(Post-study 
Safety 
Follow-up) v 
Week 18/ 
(1-Month Post-
study Safety 
Follow-up) w 
Study Day 
-35 to -1 
-7 to -1 
1 
15 (-4 /+7)  
43 ± 7  
71 ± 7  
99 (-4 
/+7)  
113 ± 7 
127 ± 7 
Visit Number 
V1 
 
V2 
V3 
V4 
V5 
V6  
V7 
V8 
Post-COVID-19 Functional 
Status (PCFS) scale 
X 
 
X 
 
 
 
X 
 
 
Insomnia Severity Index (ISI) 
 
 
X 
 
 
 
X 
 
 
Epworth Sleepiness Scale 
(ESS) i 
 
 
X 
X 
X 
X 
X 
 
 
Clinical laboratory tests k 
X 
 
 
 
X 
 
X 
 
 
Viral laboratory testing l 
X 
 
 
 
 
 
 
 
 
Drug screen 
X m 
 
 
 
 
 
 
 
 
Serum pregnancy test n 
(processed by central lab) 
X 
 
 
 
 
 
 
 
 
Urine pregnancy test n 
(processed in-clinic) 
 
 
X 
X 
X 
X 
X 
 
 
Vital signs o 
X 
 
X 
X 
X 
X 
X 
 
 
12-lead electrocardiogram p 
X 
 
 
 
 
 
 
 
 
Randomization criteria and 
procedures 
 
 
X 
 
 
 
 
 
 
Patient training and eDiary 
review q 
X 
 
X 
X 
X 
X 
X 
 
 
eDiary assessment of 24-hour 
recall of worst Long COVID 
pain and sleep quality (daily) 
r 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense double-blind study 
drug s 
 
 
X 
X 
X 
X 
 
 
 
Study drug compliance 
 
 
 
X 
X 
X 
X 
 
 
Pharmacogenomic blood 
draw (optional) t 
 
 
* 
* 
* 
* 
* 
 
 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
Assess diary compliance 
 
 
X 
X 
X 
X 
X 
 
 
Abbreviations: C-SSRS = Columbia-Suicide Severity Rating Scale; COVID-19 = Coronavirus diseas-19; ECG = electrocardiogram; ESS = Epworth Sleepiness Scale; ET 
= Early Termination; ISI = Insomnia Severity Index; mMBM = modified Michigan Body Map; MSI-BPD = McLean screening instrument for borderline personality disorder; 
PCFS = Post-COVID-19 Functional Status;; PGI-C = Patients’ Global Impression of Change; PROMIS = Patient Reported Outcomes Measurement Information System; SARS-
CoV-2 = severe acute respiratory syndrome coronavirus 2; V = Visit; WHO = World Health Organization. 
a  Patients will be required to stop all excluded medications or begin down titration, if needed before discontinuation. Washout should be completed by 
Day -21 so there is a 14-day drug-free interval prior to the beginning of the collection of Baseline diary data that takes place during the 7 days leading up to 


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the Baseline/Randomization Visit. Patients will return for an unscheduled visit after the first 2 weeks of Washout have been completed; generally, this can 
be done at Day -8 or earlier.  
b  Patients who discontinue from the study before completing the Week 14 Visit will be asked to return to the site for an Early Termination (ET) Visit to have 
Week 14 assessments completed. 
c  Any additional (pre-screening) medical findings or medications discovered after the Screening Visit are to be noted in the medical history, 
Prior/Concomitant Medication Pages, respectively. 
d  A full physical examination, including measurement of height and weight and calculation of the body mass index, will be performed at Screening.  
e  A brief physical examination will be performed at Baseline and Week 14/ET. For patients for whom a telephone visit is being conducted for Week 14/ET, 
the brief physical exam will not be required.  
f  There will be a thorough examination (visual and palpation) of the oral cavity at the Screening Visit and then visual examinations at all other in-clinic visits. 
For visits at which a visual exam is not possible (ie, telephone visit), the visual oral cavity exam is not required; in lieu of the in-clinic (or home visit) oral 
cavity exam, after conclusion of “any changes in your medical condition”, ask specifically if there have been any changes or problems in the oral cavity. 
Patients reporting any concerning lesion description or painful processes in the oral cavity possibly related to study drug exposure should be strongly urged 
to come into clinic for an Unscheduled Visit for oral cavity exam. In circumstances in which, due to the COVID-19 pandemic, it is not possible for the 
patient to return to the clinic for the Unscheduled Visit exam, a clinician certified by the Sponsor to conduct oral cavity examination should contact the 
patient by phone and obtain greater history and description of the oral cavity AE by patient, potentially augmented with images of oral cavity taken by the 
patient and sent to the site for the examining clinician to textually document in the source. In addition to the regularly scheduled in-clinic examinations, an 
unscheduled examination of the oral cavity in-clinic should be performed any time a patient contacts the clinic to report an oral cavity lesion or other oral 
AE possibly related to study drug exposure, other than oral numbness, tingling, or noticeable taste (eg, bitter, metallic, or unpleasant) after dosing, which do 
not require unscheduled examinations. 
g  The Screening version of the mMBM will be administered. 
h  The Baseline/Post-Randomization version of the mMBM will be administered. 
i  For telephone visits, the patient will be mailed all applicable patient reported outcomes for a given visit. 
j  Weekly recall of daily average Long COVID pain intensity on the NRS scale is required at the Screening Visit. Patients should only continue screening if 
they score ≥ 4 and ≤ 9.  
k  Clinical laboratory tests will be performed at Screening, Week 6, Week 14/ET. TSH, ESR, and HbA1c will be tested at Screening only.  
l  Human immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B surface antigen (HBsAg) testing will be performed at Screening and may be 
performed at other visits, at the discretion of the Investigator or Sponsor. Medical Monitor approval is required for repeat testing. 
m  The urine drug screen is mandatory at Visit 1. If the screening urine drug screen (UDS) is positive for opioids, benzodiazepines, or amphetamines and 
washout is appropriate, the patient will need to return to the clinic for an unscheduled UDS prior to the beginning of the 7-day baseline data collection phase 
leading up to Visit 2. Opioid and stimulant retesting can be performed with an in-clinic UDS, whereas the UDS must be analyzed centrally in patients 
washing off of benzodiazepines. Urine drug screening may be repeated at the Investigator’s discretion at any time. 
n  A serum pregnancy test will be performed at Screening, followed by in-clinic urine pregnancy tests at Baseline, Week 2, Week 6, Week 10, and 
Week 14/ET for women of child-bearing potential. For patients for whom a telephone visit is being conducted, the urine pregnancy test will be performed 
by the patient at home.  
o  Vital signs (oral temperature, sitting blood pressure and heart rate [obtained after resting for 5 minutes in a sitting position]) will be measured at each visit. 
For patients for whom a telephone visit is being conducted, the vital signs will not be required. 
p  A 12-lead electrocardiogram will be obtained at Screening. All electrocardiograms will be performed and interpreted locally. 
q  Clinic staff members will train the patient on how to take the study drug and how to complete an electronic diary (eDiary). In addition, patients will be 
asked to complete a brief training on accurate pain reporting and placebo response reduction training at each study visit. Patients will be asked to complete 


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their eDiary every evening. eDiary completion will start on the evening of Visit 1 and continue through Week 14. eDiary responses will be monitored 
during the study. 
r  Patients will assess their worst daily Long COVID pain over the last 24 hours every evening using an 11-point (0–10) numerical rating scale. Patients 
should be instructed to complete their diary responses in the evening, but before taking their bedtime dose of study drug. The 24-hour recall interval will 
assess the previous night’s sleep and symptoms of pain since bedtime the previous night. 
s  The study drug will be dispensed to patients at Baseline on Day 1 (following randomization) and at Weeks 2, 6, and 10. One bottle will be dispensed on 
Day 1, and two bottles will be dispensed at Weeks 2, 6, and 10. For patients for whom a telephone visit is being conducted, the study drug will be mailed 
via courier to their home. Patients will be instructed to take 1 tablet of study drug sublingually every evening at bedtime for 2 weeks starting the evening of 
Day 1, and then 2 tablets sublingually every evening from Week 2 to Week 14. 
t  * The blood draw for the pharmacogenomic assessment can be obtained at any study visit post-Screening (including an ET Visit). Due to circumstances 
caused by the COVID-19 pandemic and the possibility of no further in-clinic visits after Baseline Visit (Visit 2), it is strongly recommended that the 
pharmacogenomics blood sample be obtained at the Baseline Visit (Visit 2). It should only be obtained one time during the study. Separate written, signed 
informed consent is required if the patient is to participate in the optional pharmacogenomic assessment.  
u  The Week 2, Week 6, and Week 10 Visits may be performed via telephone only when an in-clinic visit is not feasible due to the COVID-19 pandemic. 
Select safety assessments specifically required in-clinic will not be required for the telephone visits (eg, vital signs and oral cavity exam). Telephone visits 
for Week 14/ET Visits are to be strongly discouraged due to inability to obtain several safety measures (eg, vital signs, physical exam, oral cavity exam, 
chemistry and hematology labs), but telephone visits will be permitted for Week 14/ET Visit if attendance of an in-clinic visit is absolutely impossible or 
refused by the patient as a result of the COVID-19 pandemic and it is not feasible for the site to conduct a home visit. 
v  Visit 7 (Week 16 or approximately 2 weeks after ET) will be a telephone visit. 
w  Visit 8 (Week 18 or approximately 4 weeks after ET) will be a telephone visit. 
x  Confirmation of prior SARS-CoV-2 infection can be obtained through either a polymerase chain reaction (PCR) or nucleic acid tests or a rapid antigen test. 
Acceptable documentation of SARS-CoV-2 infection may be through either a laboratory report or formal documentation either generated at the point-of-
care or by a virtual at-home test proctor/telehealth service. 
 
 
 
 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............21 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................26 
5. 
INTRODUCTION ......................................................................................................29 
5.1. 
Overview of PASC .....................................................................................................29 
5.1.1. 
Definition and Characteristics ....................................................................................29 
5.1.2. 
PASC and Fibromyalgia .............................................................................................30 
5.2. 
Background of TNX-102 SL ......................................................................................31 
5.3. 
Scientific Rationale .....................................................................................................32 
5.3.1. 
Case Definition of Multi-Site Pain Associated with PASC ........................................32 
5.3.2. 
TNX-102 SL in the Treatment of Fibromyalgia .........................................................35 
5.4. 
Rationale for Dose Selection ......................................................................................35 
5.5. 
Conclusion ..................................................................................................................36 
6. 
TRIAL OBJECTIVES ................................................................................................37 
6.1. 
Primary Objective .......................................................................................................37 
6.2. 
Secondary Objective ...................................................................................................37 
7. 
INVESTIGATIONAL PLAN .....................................................................................38 
7.1. 
Overall Study Design ..................................................................................................38 
7.2. 
Study Endpoints ..........................................................................................................39 
7.2.1. 
Primary Efficacy Endpoint .........................................................................................39 
7.2.2. 
Secondary Efficacy Endpoints ....................................................................................40 
7.2.3. 
Exploratory Efficacy Endpoints .................................................................................40 
7.2.4. 
Safety ..........................................................................................................................41 
7.3. 
Number of Patients and Treatment Assignment .........................................................41 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................42 
8.1. 
Informed Consent .......................................................................................................42 
8.2. 
Patient Inclusion Criteria ............................................................................................42 
8.3. 
Patient Exclusion Criteria ...........................................................................................43 


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8.4. 
Randomization Criteria ...............................................................................................46 
8.5. 
Patient Withdrawal Criteria ........................................................................................46 
9. 
TREATMENT OF PATIENTS ..................................................................................47 
9.1. 
Prior and Concomitant Medications ...........................................................................47 
9.2. 
Alcohol and Cannabis/THC Use ................................................................................48 
9.3. 
Enrollment of Patients ................................................................................................48 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................49 
10.1. 
Study Drug Packaging, Labeling, and Storage ...........................................................49 
10.2. 
Dosing Instructions .....................................................................................................49 
10.3. 
Dispensing Instructions ..............................................................................................50 
10.4. 
Release of Clinical Study Supplies to the Investigator ...............................................50 
10.5. 
Study Drug Accountability and Reconciliation ..........................................................50 
11. 
STUDY VISITS..........................................................................................................52 
11.1. 
Visit 1 (Screening Visit: Day -35 to Day -7) ..............................................................52 
11.1.1. 
Informed Consent .......................................................................................................52 
11.1.2. 
Screening Overview ....................................................................................................52 
11.1.3. 
Patient Numbering ......................................................................................................53 
11.1.4. 
Screening Assessments and Procedures .....................................................................53 
11.2. 
Visit 2 (Baseline: Day 1) ............................................................................................54 
11.2.1. 
Randomization Criteria ...............................................................................................54 
11.2.2. 
Baseline Visit ..............................................................................................................55 
11.2.3. 
Study Drug Dispensing ...............................................................................................56 
11.2.4. 
Patient Instructions .....................................................................................................56 
11.3. 
Visit 3 (Week 2) ..........................................................................................................57 
11.4. 
Visit 4 (Week 6) ..........................................................................................................58 
11.5. 
Visit 5 (Week 10) ........................................................................................................60 
11.6. 
Visit 6 (Week 14 or Early Termination) .....................................................................62 
11.6.1. 
Visit 6 (Week 14) ........................................................................................................62 
11.6.2. 
Early Termination (Post-Randomization) ...................................................................63 
11.7. 
Visit 7 (Week 16/Post-study Safety Follow-up) .........................................................65 
11.8. 
Visit 8 (Week 18/1-Month Post-study Safety Follow-up) ..........................................66 
11.9. 
Unscheduled Visit .......................................................................................................66 


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12. 
STUDY ASSESSMENTS ..........................................................................................67 
12.1. 
Efficacy Assessments .................................................................................................67 
12.1.1. 
Modified Michigan Body Map ...................................................................................67 
12.1.2. 
Sheehan Disability Scale (SDS) .................................................................................68 
12.1.3. 
PROMIS Scales ..........................................................................................................68 
12.1.4. 
Patient Global Impression of Change (PGI-C) ...........................................................69 
12.1.5. 
Post-COVID-19 Functional Status (PCFS) scale .......................................................69 
12.1.6. 
Insomnia Severity Index (ISI) – Patient version .........................................................69 
12.1.7. 
Epworth Sleepiness Scale (ESS) ................................................................................69 
12.1.8. 
eDiary .........................................................................................................................69 
12.2. 
Safety Assessments .....................................................................................................70 
12.2.1. 
Adverse Events ...........................................................................................................70 
12.2.2. 
Oral Adverse Events ...................................................................................................71 
12.2.3. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................71 
12.2.4. 
Physical Examination and Vital Signs ........................................................................72 
12.2.5. 
Visual Examination of the Oral Cavity ......................................................................72 
12.2.6. 
Clinical Laboratory Assessments ...............................................................................72 
12.2.7. 
Electrocardiogram .......................................................................................................74 
12.3. 
Pharmacogenomic Testing (Optional) ........................................................................75 
13. 
STATISTICAL CONSIDERATIONS AND ANALYSES ........................................76 
13.1. 
Populations for Analysis .............................................................................................76 
13.2. 
Estimate of Sample Size .............................................................................................76 
13.3. 
Assessment of Demographic and Baseline Characteristics ........................................77 
13.4. 
Efficacy Analyses .......................................................................................................77 
13.4.1. 
Primary Efficacy Analysis ..........................................................................................77 
13.4.2. 
Missing Data Imputation ............................................................................................77 
13.5. 
Sensitivity Analyses ....................................................................................................78 
13.6. 
Secondary Efficacy Analyses .....................................................................................78 
13.6.1. 
Exploratory Efficacy Analyses ...................................................................................79 
13.7. 
Safety Analyses ..........................................................................................................79 
13.8. 
Interim Analyses .........................................................................................................81 
13.8.1. 
P-value Adjustment for the Interim Analysis .............................................................82 


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14. 
DEFINITIONS, RECORDING, AND REPORTING OF ADVERSE 
EVENTS .....................................................................................................................83 
14.1. 
Definition of Adverse Events .....................................................................................83 
14.2. 
Adverse Event Recording ...........................................................................................83 
14.2.1. 
Coding the Adverse Event ..........................................................................................83 
14.2.2. 
Severity of Adverse Event ..........................................................................................83 
14.2.3. 
Relationship of Adverse Events to Study Drug ..........................................................84 
14.3. 
Serious Adverse Events (SAEs) and Serious Adverse Drug Reactions .....................84 
14.4. 
Pregnancy ...................................................................................................................86 
15. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY .................................................................................87 
15.1. 
Protocol Modifications and Deviations ......................................................................87 
15.2. 
Study Termination ......................................................................................................87 
16. 
ETHICAL CONSIDERATIONS................................................................................88 
16.1. 
Ethical Conduct of the Study ......................................................................................88 
16.2. 
Ethics Committee/Institutional Review Board (EC/IRB) Review .............................88 
16.3. 
Written Informed Consent ..........................................................................................88 
17. 
DATA HANDLING, RECORD KEEPING, MONITORING AND AUDITS ..........90 
17.1. 
Maintaining Privacy and Confidentiality....................................................................90 
17.2. 
Maintaining Essential Clinical Documents ................................................................90 
17.3. 
Data Handling .............................................................................................................90 
17.4. 
Case Report Forms (CRFs) .........................................................................................91 
17.5. 
Clinical Laboratory Certification ................................................................................91 
17.6. 
Site Monitoring and Tonix’s Right to Review Records .............................................91 
17.7. 
Audits and Inspections ................................................................................................92 
18. 
CONFIDENTIALITY ................................................................................................93 
18.1. 
Protection of Patient Anonymity ................................................................................93 
18.2. 
Confidentiality of Study Information .........................................................................93 
18.3. 
Publication of Data and Protection of Trade Secrets ..................................................93 
19. 
REFERENCES ...........................................................................................................94 
20. 
APPENDICES ............................................................................................................98 
 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Study Design and Schedule of Assessments ..............................................................17 
Table 3: 
Clinical Laboratory Assessments ...............................................................................74 
Table 4:  
Relationship between pain sites and body regions ...................................................101 
 
LIST OF FIGURES 
Figure 1:  Michigan Body Map ...................................................................................................33 
Figure 2:  Functional Status* of Patients Undergoing Arthroplasty by Number of Pain 
Sites at Baseline ..........................................................................................................34 
 
 
 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Term 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CBP 
cyclobenzaprine HCl 
CFR 
Code of Federal Regulations 
CFS 
chronic fatigue syndrome 
CGRP 
calcitonin gene-related peptide 
CI 
confidence interval 
CK 
creatine kinase 
COVID-19 
Coronavirus Disease 2019 - viral illness caused by SARS-CoV-2  
CRF 
case report form 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP3A4 
cytochrome P450 subtype 3A4 
DDFM 
denominator degrees of freedom 
eg 
exempli gratia (for example) 
EC 
ethics committee 
ECG 
electrocardiogram 
ER 
extended release 
ESS 
Epworth Sleepiness Scale 
ET 
Early Termination (ie, discontinuation from trial) 
etc. 
et cetera (and other things) 
FDA 
US Food and Drug Administration 
FM 
fibromyalgia 
g 
gram(s) 
GCP 
good clinical practice 
GLP 
good laboratory practice 
h 
hour(s) 
HbA1c 
glycated hemoglobin  
HBsAg 
hepatitis B surface antigen 
HCl 
hydrochloride 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ie 
id est (that is) 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 


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Term 
Definition 
IND 
Investigational New Drug (application) 
IR 
immediate release 
IRB 
institutional review board 
IRT 
Interactive Response Technology 
ISI 
Insomnia Severity Index 
ITT 
intention-to-treat 
kg 
kilogram(s) 
L 
liter(s) 
LOE 
lack of efficacy 
LS 
least square (mean) 
MAR 
missing at random 
MBM 
Michigan Body Map 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCMC 
Markov Chain Monte Carlo 
MCV 
mean corpuscular volume 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
mg 
milligram(s) 
MI 
multiple imputation  
min 
minute(s) 
MINI 
Mini International Neuropsychiatric Interview 
mL 
milliliter(s) 
mMBM 
modified Michigan Body Map 
MMRM 
mixed-effects model repeated-measures 
MNAR 
missing not at random 
msec 
millisecond(s) 
MSI-BPD 
McLean Screening Instrument for BPD 
N, n 
number (of patients) 
NA 
not applicable 
NDA 
New Drug Application 
ng 
nanogram(s) 
NRS 
numeric rating scale 
NSAID 
nonsteroidal anti-inflammatory drug 
PASC 
post-acute Sequelae of SARS-CoV-2 Infection 
PCFS 
Post-COVID-19 Functional Status Scale 
PCR 
polymerase chain reaction 
PGI-C 
Patient Global Impression of Change 
PI 
Principal Investigator 
PRO 
patient-reported outcome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PTSD 
post-traumatic stress disorder 
QTcF 
QT corrected for heart rate using Fridericia’s formula 
RBC 
red blood cell 


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Term 
Definition 
R/O 
Rule out 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 – the virus that causes 
viral illness known as COVID-19 
SAS 
Statistical Analysis System 
SDS 
Sheehan Disability Scale 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SL 
sublingual 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TID 
three times daily 
THC 
tetrahydrocannabinol 
TNX-102 SL  
cyclobenzaprine HCl sublingual tablets  
TSH 
thyroid-stimulating hormone 
UDS 
urine drug screen 
US 
United States 
VHA 
Veterans Health Administration 
vs 
versus 
WBC 
white blood cell 
WHO 
World Health Organization 
WPI 
Widespread Pain Index 
 
 
 


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5. 
INTRODUCTION 
5.1. 
Overview of PASC 
5.1.1. 
Definition and Characteristics 
A set of symptoms experienced by people with a history of probable or confirmed SARS-CoV-2 
infection, usually 3 months from the onset of Coronavirus Disease 2019 (COVID-19), with 
symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis, has 
been termed Post-acute Sequelae of SARS-CoV-2 infection (PASC) (colloquially known as 
“Long COVID” or “long haulers”). Common symptoms include fatigue, shortness of breath, and 
cognitive dysfunction, as well as others that generally have an impact on everyday functioning. 
Symptoms may be new onset, following initial recovery from an acute COVID-19 episode, or 
persist from the initial illness. Symptoms may also fluctuate or relapse over time (World Health 
Organization; WHO 2021). 
The lack of a standardized definition for PASC makes it difficult to determine the exact 
epidemiology, incidence rates, and the impact of the condition on long-term disability. A 
conservative estimate based on data collected from numerous countries is that, on average, 30% 
(range 32.6% to 87.4%) of people with COVID-19 experience PASC (summarized in 
Nalbandian et al. 2021).  
The WHO-endorsed definition states that PASC occurs in individuals with a history of probable 
or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with 
symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. 
Therefore, PASC can broadly be described as the presence of one or more symptoms (continuous 
or relapsing/remitting; new or same symptoms of acute COVID-19) in individuals who have 
been infected with SARS-CoV-2 after the expected period of clinical recovery (Raveendran et al. 
2021).  
Symptoms of PASC have been variably reported as including fatigue, muscle weakness, 
diaphoresis, myalgia, arthralgia, chills, limb edema, dizziness, post-exertional malaise, cognitive 
dysfunction, respiratory symptoms (polypnea, chest pain, cough, sputum, sore throat), 
cardiovascular abnormalities, alopecia, olfactory abnormalities, psychosocial symptoms (such as 
sleep difficulties, depression, anxiety, feelings of inferiority), and generally a worse quality of 
life (Gagnier et al. Submitted; Davis et al. 2021; Lambert et al 2021; Bierle et al. 2021; Crook et 
al. 2021; Raveendran et al. 2021).  
Fatigue is the most common symptom reported in PASC patients, occurring in roughly 40% to 
80% of patients at an average of 4 to 8 weeks post-onset (Crook et al. 2021; Davis et al. 2021; 
Lambert et al 2021; Lopez-Leon et al. 2021; Bierle et al. 2021). In a telephone study performed 
in the United States (US), of 488 patients, 32.6% reported persistent symptoms at 60 days 
post-discharge from the hospital, including 18.9% with new or worsened symptoms (Chopra et 
al. 2020). Fatigue has been reported in 77.7% of those with symptoms at 6 months post-
infection, according to a survey disseminated via email, social media, and online patient support 
groups (Davis et al. 2021).  
Muscle pains and aches were reported in 43.7% of those with symptoms at 6 months post-
infection (Davis et al. 2021). The authors noted that PASC features involving pain occurred more 


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commonly than any of the other features (34.2%), and occurred more commonly than after 
influenza (24.0%). Also, pain was the only feature that had a higher incidence in the 3- to 6-
month period than in the 0- to 3-month period. The authors conclude that pain appears to be a 
prominent and relatively persistent element of PASC (Taquet et al. 2021).  
Clauw and colleagues from University of Michigan are currently conducting a study to: (1) 
understand the experience of PASC among those who are Black or African American; and (2) 
identify factors that support or hinder their ability to manage and cope with PASC symptoms. 
Data are collected using semi-structured interviews that are visually and/or audio recorded. Of 
those who have participated in the study thus far, a third have reported pain symptoms. Some 
patients reported swelling and pain in joints, either as an exacerbation of previous pain or as new 
pain. The interviews revealed that the pain manifests mostly as headaches/facial pain, back pain, 
and joint pain and that it is either persistent or occurs in relapsing episodes. The pain was 
associated with significant distress, functional impairments, and decrease in quality of life 
(Clauw et al. Data on File/ Personal Communication).  
A variety of sleep disturbances have also been reported in PASC. In one report, nearly 80% of 
PASC patients experienced sleep disturbances, including insomnia, difficulty falling asleep, 
vivid/lucid dreams, and nonrestorative sleep (Davis et al. 2021). 
Al-Aly and colleagues reported on the burden of PASC in a large cohort that included 73,435 
users of the Veterans Health Administration (VHA) with COVID-19 who survived for at least 
the first 30 days after their COVID-19 diagnosis and who were not hospitalized vs nearly 
5 million VHA users who were hospitalized but not for COVID-19. Individuals with COVID-19 
exhibited an excess burden of poor general well-being, including sleep-wake disorders (hazard 
ratio 14.53 [confidence interval (CI) 11.53−17.36]), malaise and fatigue (12.64 [11.24–13.93]), 
musculoskeletal pain (13.89 [9.89−17.71]), muscle disorders (5.73 [4.60–6.74]), and arthralgia 
and arthritis (5.16 [3.18–7.01]) (Al-Aly et al. 2021). 
Therefore, PASC symptoms span multiple organ systems and may have significant effects on 
physical and mental health, functional status, and quality of life. 
5.1.2. 
PASC and Fibromyalgia  
Among the symptoms that characterize PASC, multi-site pain, sleep disturbances, and fatigue 
have been reported in several longitudinal studies of PASC (Lambert et al 2021; Davis et al. 
2021; Bierle et al. 2021). This has prompted several groups to propose that PASC may be a 
condition similar to other central sensitization/nociplastic pain syndromes, such as fibromyalgia 
(FM), chronic fatigue syndrome (CFS), or postural orthostatic tachycardia syndrome (Bierle et 
al. 2021; Ursini et al. 2021; Clauw et al. 2020). 
Multi-site pain in association with fatigue and cognitive and sleep disturbances, such as observed 
in patients with PASC, is a characteristic feature of FM (Mease et al. 2009). Pain associated with 
FM and other complex regional pain syndromes are generally independent of underlying tissue 
damage and are believed to reflect abnormalities of central pain perception (Fitzcharles et al. 2021; 
Minhas et al. 2021; Kosek et al. 2021).  
A connection between PASC and FM has been proposed by other groups. Based on their analysis 
of patient appointment request documentation for 465 people with confirmed or suspected 


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COVID-19 infection, Bierle and colleagues identified a subset of 42 (9%) patients who met 
criteria for a significant post-viral syndrome with central sensitization, which they termed 
Post-COVID Syndrome (PoCoS). Furthermore, they proposed that, if these symptoms persist 
past 6 months, these patients may meet the clinical definition of one of the central sensitization 
syndrome disorders, such as FM, CFS, or postural orthostatic tachycardia syndrome (Bierle et al. 
2021).  
In a web-based survey distributed through social networks, Ursini and colleagues collected 
information from people who have had COVID-19 diagnosis 6 ± 3 months earlier using the 
American College of Rheumatology 2010 FM Survey Criteria modified for self-administration. 
They found that, of the 616 responders, 189 (30.7%) met the criteria for FM after an average of 
6 months since COVID-19 diagnosis (Ursini et al. 2021).   
We hypothesize that chronic multi-site pain reported in PASC patients involves 
pathophysiological mechanisms similar to those of FM and nociplastic pain (Clauw et al. 2020; 
Bierle et al. 2021; Ursini et al. 2021; Fitzcharles et al. 2021; Minhas et al. 2021; Kosek et al. 
2021) and will therefore respond to treatments that are effective in FM.  
5.2. 
Background of TNX-102 SL 
TNX-102 SL (cyclobenzaprine HCl sublingual tablets) is being developed through 505(b)(2) 
New Drug Applications (NDAs) for FM, post-traumatic stress disorder (PTSD), Agitation in 
Alzheimer’s Disease, and Alcohol Use Disorder using AMRIX (extended release [ER] capsule, 
30 mg; AMRIX® Prescribing Information, 2019) as the reference listed drug. We are currently 
also developing TNX-102 SL for the treatment of multi-site pain in PASC.  
The TNX-102 SL is a formulation containing 2.8 mg cyclobenzaprine HCl [3-(5H-
dibenzo[a,d]cycloheptene-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride] for 
sublingual (SL) administration. The active ingredient in TNX-102 SL, cyclobenzaprine HCl 
(CBP), has been approved for use in the US since 1977, originally as FLEXERIL® 10-mg oral 
tablets indicated as an adjunct to rest and physical therapy for the relief of muscle spasm 
associated with acute, painful musculoskeletal conditions. The usual dose for this indication is 
30 mg or 15 mg per day taken as 10 mg three times daily (TID) or 5 mg TID, respectively 
(FLEXERIL® Prescribing Information, 2013). The FLEXERIL® brand of immediate-release (IR) 
CBP tablets was discontinued in May 2013. Generic CBP is available and marketed in a variety 
of strengths, including 5-, 7.5- and 10-mg IR tablets. AMRIX® (AMRIX® Prescribing 
Information, 2019), an ER capsule of CBP, was approved in 2007 in the US through an NDA 
and is currently available in 15 and 30 mg, taken once a day for the same indication as 
FLEXERIL® in the US. Both FLEXERIL® and AMRIX® are indicated for 2–3 weeks use only. 
No CBP product has been approved for use in PASC by the Food and Drug Administration 
(FDA), Health Canada, or in any other country. 
In addition to its therapeutic effects on muscle spasm, CBP also exhibits functional antagonism 
of 5 HT2A, α1-adrenergic, H1-histaminergic, and M1-muscarinic acetylcholine receptors, and 
these actions may underlie its putative ability to improve sleep quality. TNX-102 SL is a 
low-dose sublingual formulation of CBP being developed to provide greater diurnal variation in 
peak-to-trough drug levels to enhance nocturnal treatment effects while minimizing daytime side 
effects. 


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TNX-102 SL is a non-opioid centrally-acting analgesic that is hypothesized to have activity that 
is mediated by targeting sleep disturbances. Prior studies performed in FM patients and PTSD 
patients saw that improvement in sleep precede and predict improvements of global symptoms of 
these disorders. Thus, given that difficulty sleeping and chronic pain are common symptoms of 
PASC, the proposed treatment with TNX-102 SL 5.6 mg taken daily at bedtime may provide 
adequate relief of PASC symptoms by promoting improvement in sleep quality, and, 
secondarily, improvement in chronic pain, fatigue, anxiety and mood, and cognitive function. 
5.3. 
Scientific Rationale 
The symptoms of PASC can roughly be divided into 4 groups, including: 1) direct organ or 
tissue damage due to the acute infection, 2) COVID-19-induced hypercoagulable states, 
3) mental health issues triggered by the infection, isolation, and disparities in health, and 4) a set 
of non-specific symptoms including multi-site pain, sleep disturbances, and fatigue (Lopez-Leon 
et al. 2021; Sudre et al. 2021; Huang et al. 2021; Clauw et al. 2020). The development program 
for TNX-102 SL (cyclobenzaprine HCl sublingual tablets) is aimed at palliation of this latter 
mechanism, focusing on identifying and treating individuals with multi-site pain due to PASC 
who display the primary symptoms observed in common overlapping pain conditions, such as 
FM, CFS, tension headache, irritable bowel syndrome, and bladder pain syndrome (Fitzcharles et 
al. 2021; Kosek et al. 2021; Larkin et al. 2021; Kratz et al. 2021). 
5.3.1. 
Case Definition of Multi-Site Pain Associated with PASC   
We define multi-site pain as chronic pain in 4 or more regions on the modified Michigan Body 
Map (mMBM; Appendix 2), a self-report measure to assess body areas of chronic pain. The 
original Michigan Body Map is depicted in Figure 1. 
In a series of studies using lower extremity arthroplasty as a model for pain originating in the 
periphery (which should be relieved with surgery), Dr. Daniel Clauw from the University of 
Michigan and his colleagues showed that, for each 1-point increase in the 2016 FM Survey 
criteria, there was a 25% decrease in response to surgery intended to relieve pain (Brummett et 
al. 2015a), and, similarly, non-responsiveness to opioids (Goesling et al. 2016). In order to 
identify a data-driven cut-off point for multi-site pain, they analyzed the data from Brummett et 
al. 2015a specifically comparing the number of pain regions (out of a possible 7, including left 
arm, right arm, left leg, right leg, front of trunk, back of trunk, and head) to the incidence of the 
other key features of pain in central sensitization (memory and sleep problems, fatigue, 
decreased functional status). They measured the participants’ ability to perform tasks (per 
PROMIS Physical Function Scale) scored on a numeric scale from 1 to 5 (see Figure 2 footnote 
for details). Before surgery (Figure 2A), the average score of ≥ 3 (“with some difficulty”) for the 
functional status measures was observed independent of the number of pain sites. Six months 
after the surgery (Figure 2B), the average scores for only those participants with ≥ 4 pain sites 
indicated at least “a little difficulty” with performing tasks (score of ≥ 2). Furthermore, they 
observed an increase in the co-morbid non-pain symptoms, such as fatigue, sleep, memory and 
cognitive function, as the number of regions affected by pain increased from 3 to 4 (Clauw et al. 
Data on file/Personal communication).  
The MBM has been used to assess widespread pain in a number of recent studies (Brummett et 
al. 2013a; Brummett et al. 2013b; Brummett et al. 2015a; Brummett et al. 2015b; Hassett et al. 


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2012; Hassett et al. 2013; Janda et al. 2015; Wasserman et al. 2014). Based on the studies of 
Clauw et al, multi-site pain, defined as pain persisting in 4 or more regions on the mMBM, 
would be indicative of the widespread pain associated with PASC. 
Figure 1:  
Michigan Body Map 
 
 


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Figure 2:  
Functional Status* of Patients Undergoing Arthroplasty by Number of Pain 
Sites at Baseline 
A. Before surgery 
 
B. Six months after surgery 
 
N = 334. 
Data are medians and interquartile ranges.  
* Functional status measures on a 4-Item PROMIS Physical Function Scale:  
PFA11 = Are you able to do chores such as vacuuming? 
PFA21 = Are you able to go up and down the stairs at a normal pace? 
PFA23 = Are you able to go for a walk for at least 15 min? 
PFA53 = Are you able to run errands and shop? 
1= without any difficulty, 2= with a little difficulty, 3= with some difficulty, 4= with much difficulty, 5= unable to do. 


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PF = [PROMIS] Physical Function [scale]. 
5.3.2. 
TNX-102 SL in the Treatment of Fibromyalgia 
One Phase 2 and two Phase 3 studies evaluated TNX-102 SL in patients with FM. Even though 
the Phase 2 study and the first Phase 3 study (TNX-CY-F301), both using 2.8 mg dose of 
TNX-102 SL, narrowly missed on their primary pain efficacy endpoint, both studies showed 
significant improvements in FM pain when analyzed by other standard statistical approaches, as 
well as significant improvements in sleep quality, Patient Global Impression of Change, and 
fibromyalgia-specific measures.  
Based on these promising results, the next Phase 3 study (TNX-CY-F304/F304) in FM used 
TNX-102 SL at the 5.6 mg dose. In this 14-week randomized, double-blind, placebo-controlled, 
multicenter Phase 3 study, 503 patients were randomized to receive either TNX-102 SL or 
placebo. For the first 2 weeks of treatment, patients started on TNX-102 SL 2.8 mg (1 tablet) or 
placebo. Starting at the Week 2, all patients had the dose increased to TNX-102 SL 5.6 mg 
(2 x 2.8 mg tablets) or 2 placebo tablets for 12 weeks of treatment. The study showed a reduction 
in the weekly average daily diary pain scores at Week 14 (primary endpoint). The treatment 
group difference (TNX-102 SL minus placebo) in daily pain reduction was statistically 
significant (p=0.010) in favor of TNX-102 SL. The primary efficacy analysis was also supported 
by an exploratory 30% responder analysis of daily diary pain (p=0.006). A second Phase 3 study 
(TNX-CY-F306/F306) with a similar design discontinued enrollment after an interim analysis 
when an independent data monitoring committee recommended to stop the study early for 
futility. The study did not achieve statistical significance on the primary endpoint in the weekly 
average daily diary pain scores at Week 14 (p=0.115), which Tonix believes was due to an 
unexpected higher rate of adverse-related discontinuations in both the active and placebo groups 
compared to prior studies of TNX-102 SL. However, there was strong activity on sleep 
disturbance (p=0.004) and on the Patient Global Impression of Change (p=0.038). Encouraged 
by these results, a third potential pivotal Phase 3 study in FM with a similar design is currently 
ongoing.  
In the studies in FM patients, the improvement in pain can be assessed by the mean change from 
Baseline to Week 14 in a score based on the self-reported 24-hour recall of average pain intensity 
using an 11-point (0–10) numeric rating scale (NRS). As in these studies, multi-site pain was 
reproducibly measured using the pain NRS diary, we intend to measure effects of TNX-102 SL 
on pain in PASC patients as measured by the NRS diary.  
5.4. 
Rationale for Dose Selection 
Previous FM Phase 2 studies and the first Phase 3 study (TNX-CY-F301) used TNX-102 SL at 
the 2.8 mg dose. Although the study did not reach statistical significance for the primary 
endpoint of 30% responder analysis in pain (p=0.095), most secondary endpoints, including 
many other common statistical analyses of pain and sleep, were nominally significant. The 
second Phase 3 study of TNX-102 SL, TNX-CY-F302, was initiated in the first half of 2016 but 
was terminated upon receipt of the negative TNX-CY-F301 study primary analysis results. The 
findings from early Phase 2 and 3 studies used TNX-102 SL at the 2.8 mg dose provided an 
opportunity to reassess the optimal dose of TNX-102 SL and the most appropriate study design 
for the subsequent Phase 3 study in FM, TNX-CY-F304. 


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To evaluate whether the efficacy of TNX-102 SL on FM pain might be greater with a dose 
higher than 2.8 mg, in-clinic pain data from the Phase 2 study (TNX-CY-P201) in patients with 
PTSD were analyzed. Study TNX-CY-P201 was more restrictive than TNX-CY-F301 in terms 
of allowable pharmacological pain therapies, with exclusion of opiates, all antidepressants, and 
other pain treatments (eg, gabapentin, pregabalin). Like TNX-CY-F301, TNX-CY-P201 allowed 
only use of acetaminophen or NSAIDs for pain control. The TNX-CY-P201 subgroup included 
in this analysis consisted of patients with Baseline NRS scores of ≥ 4 for in-clinic assessments of 
average pain over the previous 24 hours, similar to the pain diary minimal pain requirement for 
randomization in the FM studies. Results showed that the TNX-102 SL 5.6 mg subgroup had the 
largest numerical improvement in pain scores at each post-baseline assessment (average 
difference from placebo in least squares mean change from Baseline across Weeks 2 through 12 
was -0.81 units), whereas the TNX-102 SL 2.8 mg subgroup was similar to placebo. Numbers of 
patients in each group were too small for appropriate power to show statistical significance of 
5.6 mg compared with placebo, but calculated effect sizes supported the effects of this dose on 
pain. The Cohen’s D effect size after 12 weeks of treatment for TNX-102 SL 5.6 mg over 
placebo was 0.34, which is a clinically meaningful reduction in pain and on par with the effect 
sizes on pain of the 3 FDA-approved pharmacotherapies for FM (Perrot and Russell. 2014). 
These results of improved analgesic response while maintaining good tolerability in PTSD at 
5.6 mg supported the notion that increasing the dose studied in FM may have a greater analgesic 
response on FM pain while maintaining an acceptable level of tolerability. 
A 5.6-mg dose of TNX-102 SL was used in the Phase 3 study F304. In Study F304, the primary 
efficacy endpoint was the change from Baseline to Week 14 in the NRS weekly average of daily 
self-reported average pain intensity scores. The treatment group difference (TNX-102 SL minus 
placebo) in pain reduction was statistically significant (p=0.010) in favor of TNX-102 SL.  
Given the overlapping symptoms of pain reported in FM and PASC, we believe that TNX-102 
SL 5.6 mg is a promising first-line therapy to treat the proposed indication of multi-site pain 
associated with PASC. 
5.5. 
Conclusion 
We propose that PASC, characterized by a triad of multi-site pain, fatigue, and sleep disturbance, 
has features of central sensitization syndromes similar to FM. We propose to investigate the 
efficacy and safety of TNX-102 SL, which has shown promising results in treating FM, as a 
treatment of multi-site pain in patients with PASC.   
 


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6. 
TRIAL OBJECTIVES 
6.1. 
Primary Objective 
To evaluate the efficacy of TNX-102 SL 5.6 mg daily at bedtime in the treatment of patients with 
multi-site pain associated with Long COVID. 
6.2. 
Secondary Objective 
To evaluate the safety and tolerability of TNX-102 SL 5.6 mg daily at bedtime in the treatment 
of multi-site pain associated with Long COVID. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 2, randomized, parallel-group, double-blind, placebo-controlled, 14-week study 
designed to evaluate the efficacy and safety of TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) taken 
once daily at bedtime for the management of multi-site pain associated with Long COVID. The 
study is to be conducted at approximately 30 investigational sites in the US.  
The study will consist of a Screening Visit (Visit 1, Days -35 to -8), a Washout and Screening 
period of at least 7 days (for those patients not requiring washout) and no more than 35 days, 
inclusive of a 7-day baseline data collection phase immediately preceding the Baseline Visit. 
Eligible patients who provide written informed consent will have study assessments performed at 
Screening. Due to limitations in the diary completion window, patients who are planning on 
international travel during the study period should not be considered for the study. Patients 
whose employment involves overnight shifts also should not be considered for the study due to 
the restricted completion window and the requirement for consistent bedtime dosing. 
At Screening Visit 1 and after signing the written informed consent, any required washout should 
be discussed with the patient and plans made for an appropriate schedule for reducing/stopping 
any excluded medications. This down-titration and discontinuation of excluded medications must 
be accomplished so that the patient is free of excluded medications for at least 14 days prior to 
beginning of the collection of Baseline diary data that takes place during the 7 days leading up to 
the Baseline/Randomization Visit. Any additional time required for down-titration would be in 
addition to this washout requirement. For extenuating circumstances, the total duration of the 
Screening period may be increased to up to a maximum of 49 days with Medical Monitor 
approval. All excluded medications will be stopped during the Washout period through the 
Week 14/ Early Termination (ET) Visit (Visit 6).  
Patients will be trained on use of an eDiary system at Visit 1.  
During the 7-day run-in Phase (7 days immediately preceding Visit 2 [Baseline/Randomization 
Visit; Day 1]) patients will be asked to record their worst daily Long COVID pain intensity on 
the 11-point (0−10) NRS scale using 24-hour recall and assess sleep quality from the previous 
evening, also using an 11-point NRS scale. The average of the 7 days immediately preceding 
Visit 2 (Baseline Randomization Visit; Day 1) will serve as the Baseline pre-treatment scores.  
After completing any required washout of excluded therapies and recording Baseline Diary 
scores for at least 7 days, patients will return to the investigative site for Baseline assessments 
and randomization (Day 1, Visit 2), when they will be randomly assigned to receive 
TNX-102 SL or matching placebo sublingual tablets in a 1:1 ratio.  
During the treatment phase, each evening, the system will prompt the patient to reflect on the 
past 24 hours and record their worst pain intensity, assess their sleep quality from the previous 
evening, and log study drug dosing from the previous night (post-randomization). 
Patients will take the study drug SL once daily at bedtime, starting on the day of randomization 
(Day 1), for 14 weeks. For the first 2 weeks of treatment, patients will start on TNX-102 SL 
2.8 mg/day (1 tablet) or placebo. Patients will continue to record their worst daily pain, assess 
their sleep quality from the previous evening, and log study drug compliance.  


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All patients will then return to the clinic at Week 2 (Visit 3) for efficacy and safety assessments 
and assessment of study drug compliance. The study drug dose will be increased to 2 tablets 
(5.6 mg; 2 x 2.8 mg TNX-102 SL tablets or placebo) or 2 placebo tablets taken SL and 
simultaneously daily at bedtime. Patients will next return to the clinic at Week 6 (Visit 4) for 
assessment of safety, efficacy, study drug compliance, and dose tolerability at the 5.6-mg dose. 
In scenarios in which TNX-102 SL 5.6 mg (or 2 placebo tablets) is considered intolerable due to 
adverse event(s) (AEs) and would otherwise lead to study discontinuation, with Medical Monitor 
approval, the Investigator may lower the daily dose to 1 tablet every night (TNX-102 SL 2.8 mg 
or 1 placebo tablet). If/when it is deemed clinically warranted by the Investigator, rechallenge 
with 2 tablets TNX-102 SL 2.8 mg (5.6 mg dose)/placebo may be attempted or the patient may 
remain on the lower dose for the remainder of the study. It will be emphasized to Investigators 
that such dosage reduction should only be considered when the patient’s intolerability is 
sufficient to cause the patient to consider discontinuing from the study. It will be emphasized to 
participating patients that they should only make changes in study drug dose upon consultation 
with the Investigator, and they should notify the clinic immediately if they think the dosage 
needs to be adjusted. Ideally, any changes in dose should only be made at a scheduled visit, but, 
if it necessary to change dose between visits, the change should only be made upon the 
recommendation of the Investigator after discussion between the patient and the Investigator.  
Patients will return to the clinic for safety, tolerability, and efficacy assessments, and 
assessments of study drug compliance at Week 2 (Visit 3), Week 6 (Visit 4), Weeks 10 (Visit 5) 
and 14 (Visit 6) or ET.  
Approximately 2 weeks after Week 14 (Visit 6), there will be a Post-study Safety Follow-up 
telephone call (Visit 7), and approximately 4 weeks after Week 14, there will be a 1-Month 
Post-study Safety Follow-up telephone call (Visit 8). 
Due to the exceptional circumstances caused by the COVID-19 pandemic, an option for a 
telephone visit will be available for Weeks 2, 6, 10 (Visits 3, 4, 5), and, only with Medical 
Monitor approval, Week 14/Visit 6 (or ET) for those unable to attend an in-clinic visit due to the 
COVID-19 pandemic. However, all visits should be conducted in person whenever possible. 
The total duration of the study, including screening and follow-up, may be as long as 25 weeks. 
The maximum treatment duration will be 14 weeks. 
Patients who wish to withdraw from the study may do so at any time. 
The study timeline and events schedule are provided in Table 2. 
7.2. 
Study Endpoints 
7.2.1. 
Primary Efficacy Endpoint 
• Change from Baseline in the diary NRS weekly average of daily self-reported worst 
Long COVID pain intensity scores at the Week 14 endpoint 


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7.2.2. 
Secondary Efficacy Endpoints 
Key Secondary efficacy endpoints:  
• Change from Baseline in the weekly average of the daily diary NRS assessment of sleep 
quality at the Week 14 endpoint  
• Change from Baseline in the PROMIS score for fatigue at the Week 14 endpoint 
• Change from Baseline in the PROMIS score for cognitive function at the Week 14 
endpoint 
 
Secondary Efficacy endpoints: 
• Change from Baseline in the Patient Reported Outcomes Measurement Information 
System (PROMIS) score for sleep disturbance at the Week 14 endpoint  
• Proportion of patients with a Patient Global Impression of Change (PGI-C) rating of 
“very much improved” or “much improved” at the Week 14 endpoint 
• Change from Baseline to Week 14 in the Sheehan Disability Scale (SDS) 
• Change from Baseline to Week 14 in the Insomnia Severity Index (ISI) 
• Change from Baseline to Week 14 in the Epworth Sleepiness Scale (ESS) 
7.2.3. 
Exploratory Efficacy Endpoints 
• Proportion of patients with a ≥ 30% improvement from Baseline to Weeks 1−14 in the 
daily self-reported worst Long COVID pain intensity score 
• Proportion of patients with a ≥ 50% improvement from Baseline to Weeks 1−14 in the 
daily self-reported worst Long COVID pain intensity scores 
• Proportion of Patients with a PGI-C rating of “very much improved” or “much 
improved” at each post-randomization clinic visit 
• PGI-C (1-7) rating at each post-randomization clinic visit 
• Change from Baseline in the PROMIS score for sleep disturbance at each 
post--randomization clinic visit 
• Change from Baseline in the PROMIS score for fatigue at each post-randomization clinic 
visit 
• Change from Baseline in the PROMIS fatigue symptom questions 1,3,4 (individually and 
summed) at each post-randomization clinic visit 
• Change from Baseline in the PROMIS fatigue impact questions 6,7,8 (individually and 
summed) at each post-randomization clinic visit 
• Change from Baseline in the PROMIS score for cognitive function at each 
post--randomization clinic visit 


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• Change from Baseline in the weekly average of the daily diary assessment of sleep 
quality at Weeks 1−14 
• Change from Baseline in the weekly average of the daily diary assessment of worst pain 
intensity scores at Weeks 1−14 
• Change from Baseline in laboratory markers of inflammation 
• Change from Baseline to Week 14 in the Post-COVID-19 Functional Status Scale (PCFS) 
• Change from Baseline in the total number of the modified Michigan Body Map pain 
regions identified as having pain at each post-randomization clinic visit 
• Change from Baseline in average NRS Long COVID pain intensity across the 7 pain 
regions in the modified Michigan Body Map at each post-randomization visit; regions 
without pain identified will be assigned a value of 0 
• Change from Baseline in average NRS Long COVID pain intensity within the index site 
region on the modified Michigan Body Map at each post-randomization visit 
• Change from Baseline in average NRS Long COVID pain intensity within the worst 
region for a given visit on the modified Michigan Body Map at each post-randomization 
visit; this will compare the value for the worst region at a visit and the worst region at 
baseline 
• Subgroup analyses of the above endpoints by severity of their SARS-CoV-2 infection 
using groupings of the WHO ordinal scale of COVID severity as data allow 
• Subgroup analyses of the above endpoints by COVID vaccine status    
7.2.4. 
Safety 
• Incidence of AEs 
• Changes from Baseline in clinical laboratory tests 
• Changes from Baseline in vital signs 
• Assessment of physical examination findings, including examinations of the oral cavity 
• Monitoring suicidality using Columbia-Suicide Severity Rating Scale (C-SSRS)  
7.3. 
Number of Patients and Treatment Assignment 
Approximately 470 patients (235 per arm) will be randomized in a 1:1 ratio to treatment with 
TNX-102 SL or placebo tablets. Randomized patients who withdraw will not be replaced. 


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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. 
Informed consent is documented by means of a written, signed, and dated informed consent form 
(ICF). Additional information is provided in Section 16.3. 
8.2. 
Patient Inclusion Criteria 
Patients enrolled in this study will be volunteer patients. Eligible patients must meet all of the 
following inclusion criteria, as assessed at Screening Visit 1: 
1. The patient is male or female, 18 to 65 years of age, inclusive. 
2. The patient has a confirmed history of SARS-CoV-2 infection at least 3 months prior to 
enrollment, based on a documented written positive viral test at the time of active infection 
through either a polymerase chain reaction (PCR) or nucleic acid tests or a rapid antigen test. 
Acceptable documentation of SARS-CoV-2 infection may be through either a laboratory 
report or formal documentation either generated at the point-of-care or by a virtual at-home 
test proctor/telehealth service. 
3. The patient has a history of COVID-19 infection with a grading of 1 to 6 on the World 
Health Organization (WHO) COVID-19 8-Category Ordinal Scale of Disease Severity 
(Appendix 1). 
4. The patient has new onset or significant worsening of pain that coincides with a prior 
COVID-19 infection. The new or worsening pain following COVID-19 infection has been 
generally present for at least 3 months post initial COVID-19 diagnosis, but no longer than 
18 months post initial COVID-19 diagnosis. 
5. The patient meets criteria for multi-site pain as defined by the mMBM closely following the 
SARS-CoV-2 infection, which includes: 
• Multi-site pain, defined as pain in at least 4 out of 7 body regions (mMBM Part 2, 
Appendix 2). 
6. The patient’s in-clinic 7-day recall NRS average daily Long COVID pain intensity score at 
Screening Visit must be ≥ 4 and ≤ 9 (Appendix 3). Exceptions are only possible with 
Medical Monitor’s approval. 
7. The patient has a PCFS score of ≥ 2 (Appendix 4) at Screening and Baseline. 
8. The patient does not have another disorder that would otherwise explain his/her pain. 
9. 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 28 days after study 
drug discontinuation: 


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a. Hormonal methods such as oral, implantable, injectable, or transdermal 
contraceptives for a minimum of one full cycle (based on the patient’s usual 
menstrual cycle period) before study drug administration; 
b. Intrauterine device; 
c. Bilateral tubal ligation 
d. Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with 
spermicidal jelly or cream); 
e. Partners of vasectomized males in stable relationships; 
f. Females involved in same sex relationships; 
g. Female patients practicing abstinence may have the birth control requirement 
waived only with Medical Monitor approval. 
10. If the patient is vaccinated against the SARS-CoV-2 virus, the patient is at least 2 weeks past 
a vaccine dose. 
11. If the patient is currently receiving any non-exclusionary pharmacologic treatments, the 
patient should be on stable doses of their treatment regimen for at least 4 weeks (except for 
allowed antidepressants, which require 90 days at stable dose) prior to randomization and 
should not be expecting dosing change during the period of the trial. 
12. The patient must be willing and able to withdraw from the following therapies for the 
duration of the study: duloxetine, milnacipran, pregabalin, gabapentin, tramadol, tapentadol, 
amitriptyline and other tricyclic antidepressants, trazodone, narcotics/opioids, naltrexone 
(including CONTRAVE®), orexin receptor antagonists, all other forms of cyclobenzaprine 
(AMRIX®, or generic equivalents), and benzodiazepines. 
13. The patient is willing and able to comply with all protocol-specified requirements. 
14. The patient is capable of reading and understanding English and has provided written 
informed consent to participate.  
8.3. 
Patient Exclusion Criteria 
Patients who meet any of the following criteria as assessed at Screening Visit 1, should be 
excluded from the study: 
1. The patient has been diagnosed with infectious or inflammatory arthritis (eg, rheumatoid 
arthritis, ankylosing spondylitis, psoriatic arthritis), systemic lupus erythematosus, gout, 
or meets criteria for another type of systemic autoimmune disease (eg, Sjogren’s disease). 
2. The patient has been diagnosed with a complex regional pain syndrome, fibromyalgia, 
failed back surgery syndrome, persistent or prevalent pain symptoms related to systemic 
disease (eg, diabetic peripheral neuropathy, post-herpetic neuropathy), untreated 
hyperparathyroidism, or a history of prior surgery, trauma, organ or tissue damage,  or 
other source of pain that, in the Investigator’s opinion, would confound or interfere with 
the assessment of the patient’s symptoms or require excluded therapies during the 
patient’s study participation. 


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3. The patient has any lifetime history of bipolar disorder, schizophrenia, schizoaffective 
disorder, or other psychotic disorder as determined at Screening either by history or by 
the Mini International Neuropsychiatric Interview, Version 7.0.2 (MINI 7.0.2) Module A 
(Major Depressive Episode), Module C (Manic and Hypomanic Episodes), Module K 
(Psychotic Disorders), and Module O (Rule Out Medical, Organic, or Drug Causes for 
All Disorders). 
4. History of or evidence for a diagnosis of borderline personality disorder (BPD) based on 
a score of ≥ 7 on the McLean Screening Instrument for BPD (MSI-BPD) at Visit 1 
(Screening).  
5. The patient is at increased risk of suicide on the basis of the Investigator’s judgment, or 
the results of the C-SSRS conducted at Screening and Baseline (eg, any C-SSRS suicidal 
behavior or C-SSRS Type 3, 4, or 5 ideation during the preceding 6 months and any 
suicidal behavior within the past 12 months). 
6. The patient has participated in any other study with TNX-102 SL. 
7. The patient has a history of COVID-19 infection with a grading of ≥ 7 on the WHO 
COVID-19 8-Category Ordinal Scale of Disease Severity (Appendix 1). 
8. Based on screening laboratory results, thyroid-stimulating hormone (TSH) > 1.5 times 
the upper limit of normal, aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) > 2 times the upper limit of normal, or glycated hemoglobin (HbA1c) > 7.5%; or, 
in the Investigator’s opinion, evidence of a clinically significant laboratory abnormality 
based on Screening laboratory tests or medical history. 
9. Diagnosed with clinically significant and currently relevant cardiac disease (eg, 
significant arrhythmia; heart block; heart failure; symptomatic coronary artery disease or 
orthostatic hypotension), recent myocardial infarction [within the past 2 years]) or QTcF 
> 450 msec (male) or > 470 msec (female) on the screening electrocardiogram (ECG). 
10. The patient currently has or has a history of a clinically significant systemic infection (eg, 
human immunodeficiency virus [HIV], hepatitis B or C). 
11. The patient is currently receiving or is expected to need systemic corticosteroids (> 5 mg 
prednisone or equivalent per day) or has received acute treatment with systemic 
corticosteroids within 28 days of the Baseline Visit, or is likely to require such treatment 
during the study. 
12. The patient has received tender point, trigger point, or other local injections with 
anesthetic agents (or corticosteroids, as per Exclusion Criterion #11) within 28 days of 
the Baseline Visit, or is unable to refrain from such injections during the study. 
13. The patient is unable to successfully washout of the following medications during 
Screening, or washout is inadvisable: monoamine oxidase inhibitors (30-day washout 
required), levomilnacipran, anticonvulsants (aside from those used as migraine 
prophylaxis), amphetamine mixed salts, weight loss agents such as phentermine and 
diethylpropion, muscle relaxants (eg, methocarbamol, baclofen, carisoprodol, 
cyclobenzaprine), stimulants (eg, methylphenidate, lisdexamfetamine, 
dextroamphetamine), mirtazapine, trazodone, nefazodone, St. John’s wort, any 


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medication known to be a strong CYP3A4 inhibitor (Appendix 5), or any of the 
medications listed in Inclusion Criterion #12.  
14. Positive results for illegal or abused substances other than cannabis/THC at Screening or 
Baseline or history of substance use disorder during the preceding 1 year as defined by 
the screening MINI 7.0.2 Module J (Substance Use Disorder). Patients who utilize 
alcohol and/or cannabis/THC but do not meet criteria for greater than MILD Alcohol Use 
Disorder in Module I (Alcohol Use Disorder) and/or MILD Cannabis Use Disorder in 
Module J in the preceding 1 year are suitable for the study provided that, in the judgment 
of the Investigator, this usage will not interfere with the patient’s ability to complete the 
study or provide reliable data. 
15. Use of chewing or dipping tobacco or betel nut in the previous 6 months. 
16. Planned use of teeth-whitening strips or prescription teeth-whitening products over the 
course of study participation. 
17. Any existing oral, medical, or dental condition that could potentially interfere with the 
sublingual administration of study drug, the tolerability of study drug or the evaluation of 
administration site reactions. 
18. Any history of severe or unexplained oral or oropharyngeal swelling or edema. 
19. The patient has any clinically significant, uncontrolled, or unstable medical or surgical 
condition that could affect his or her ability to participate in the study or potentially 
compromise his or her well-being during the study. Patients with history of malignancy 
within 5 years of screening (other than treated carcinoma in situ of the cervix, basal cell 
carcinoma or Type 1 squamous cell carcinoma of the skin) must receive Medical Monitor 
approval prior to randomization. 
20. The patient has an anticipated need for surgery that might confound results or interfere 
with his or her ability to comply with the protocol. 
21. The patient is pregnant or nursing. 
22. The patient has a hypersensitivity to cyclobenzaprine or the excipients in TNX-102 SL or 
placebo formulations or any contraindications to the use of cyclobenzaprine (such as 
history of urinary retention or increased intraocular pressure). 
23. The patient has a seizure disorder or neuropathic pain that requires anticonvulsant 
therapy. 
24. 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 continuous positive airway 
pressure or oral device, are allowed at the discretion of the Investigator.  
25. The patient has a BMI > 38.0 kg/m2 (due to the increased risk of sleep apnea). 
26. The patient has a history of narcolepsy, cataplexy, restless leg syndrome, periodic 
involuntary limb movement disorder or other documented, clinically significant sleep 
disorder.  


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27. The patient has plans for international travel or has a work schedule (eg, requiring night 
shifts) that prevents them from being able to utilize the diary system during its available 
time window or to take study medication on a regular basis. 
28. The patient is currently being treated with immunosuppressive medication, sodium 
oxybate, ketamine, esketamine, or calcitonin gene-related peptide (CGRP) receptor 
antagonists. 
29. The patient has received an investigational CGRP receptor antagonist within 90 days of 
Screening, or any other investigational drug within 30 days of Screening. 
30. The patient is currently receiving other therapies to treat acute COVID-19 symptoms or 
severity, such as convalescent plasma, remdesivir, or dexamethasone 
31. The patient has another active systemic bacterial or fungal infection, or the patient is 
taking medications to treat another type of active infection 
8.4. 
Randomization Criteria 
Only those patients meeting all of the following randomization criteria at Visit 2 are eligible for 
randomization: 
1. Continues to meet all inclusion and exclusion criteria, including urine and blood test 
results, and is successfully and consistently utilizing the diary system. 
2. Patient’s pain satisfies the following criteria, as assessed by diary pain scores (24-hour 
recall): 
a.  A mean worst daily Long COVID pain intensity score ≥ 4 and ≤ 9 on the 11-point 
(0−10) NRS for the 7 days immediately preceding Visit 2, and 
b.  No more than 2 individual days with a Long COVID pain score < 4 on the 7 days 
immediately preceding Visit 2, and 
c.  No score of 10 on any of the 7 days immediately preceding Visit 2, and  
d.  Long COVID pain scores recorded on at least 5 out of the 7 days immediately 
preceding Visit 2. 
8.5. 
Patient Withdrawal Criteria 
In accordance with the Declaration of Helsinki, 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 11.6.2. 


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9. 
TREATMENT OF PATIENTS 
9.1. 
Prior and Concomitant Medications 
Patients who are taking certain medications are eligible for the study if they are willing and able, 
and it is medically reasonable, for them to be withdrawn from these medications prior to 
randomization and then refrain from usage during this study. The specific medications that must 
be withdrawn include duloxetine, milnacipran, pregabalin, gabapentin and other forms of 
anticonvulsants, tramadol, tapentadol, amitriptyline and other tricyclic antidepressants, 
trazodone, narcotics/opioids, naltrexone (including CONTRAVE®), all other forms of 
cyclobenzaprine (AMRIX®, or generic equivalents), orexin receptor antagonists, and 
benzodiazepines.  
Therapies used to treat acute COVID-19 symptoms or severity, such as convalescent plasma, 
remdesivir, or dexamethasone will be prohibited. 
Due to the exclusion of all opioids (including tramadol and tapentadol) during the treatment 
phase of the study, patients requiring opioids on a regular or frequent basis for any indication 
should not be considered. In addition, patients who are taking gabapentin, pregabalin, or any 
other anticonvulsant due to neuropathic pain should not be considered. 
Other prescription or over-the-counter medication not specifically excluded by entry criteria may 
be continued during the study, provided that the patient has been on this medication at a stable 
dose for at least 4 weeks (except for allowed antidepressants, which require 90 days at stable 
dose) prior to randomization and is not expecting to change dosages during the period of the 
study. 
In addition, certain other medications will also be prohibited and may require washout or 
exclusion of the patient if washout is not appropriate (eg, trazodone, mirtazapine, 
levomilnacipran, nefazodone, benzodiazepines, non-benzodiazepine sleep aids, stimulants, 
sodium oxybate, ketamine, esketamine, etc.).  
Patients using teeth-whitening products such as whitening strips or prescription whitening 
products must agree to discontinue their use from the day of randomization until the end of their 
study participation. 
After randomization, sedating antihistamines (eg, diphenhydramine, hydroxyzine) can be used as 
needed for insomnia; however, patients must be able to discontinue them during the Screening 
phase and must refrain from their use during the week of baseline data collection preceding 
Visit 2. The use of sedating anti-histamines after randomization should always be under the 
direction of the Investigator, and such use should be minimized to no more than a few nights in a 
row, followed by attempts to refrain from use.    
The use of non-prescription nutraceuticals such as melatonin, ramelteon, and valerian root is not 
restricted.   
New medications that are deemed required, in the opinion of the Principal Investigator or another 
physician, will be allowed, including medications needed to treat AEs. If there is a requirement 
for acute opioids, corticosteroids, or other treatments that could confound the evaluation of pain 
throughout the treatment period, the Investigator may consult with the Medical Monitor to 


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potentially delay the study visit until the medication is no longer needed. At a minimum, no 
opioid/narcotic should have been utilized within 2 days of a study visit, and ideally there will 
have been no usage during the 7 days prior to any visit, since important efficacy data will be 
collected on the diary during the week leading up to each visit.    
Rescue medications used by patients throughout the study will be identified and documented 
during study visits. 
9.2. 
Alcohol and Cannabis/THC Use 
Patients utilizing cannabis/THC and alcohol are to be excluded if MINI 7.0.2 Module J criteria 
are met for greater than MILD Cannabis Use Disorder or greater than MILD Alcohol Use 
Disorder in Module I during the preceding 1 year (prior to the Screening Visit), OR if the 
Investigator is concerned that the patient’s use of cannabis/THC or alcohol could interfere with 
patient’s ability to provide reliable data or comply with the protocol. Cannabis/THC and alcohol 
use is otherwise allowed, with caution. The screening drug screen will also test for THC to 
provide the Investigator with information regarding exposure, and to ensure that all usage is 
disclosed and taken into consideration when conducting MINI Module J. 
9.3. 
Enrollment of Patients 
Before undergoing any study-related screening procedures, each potential patient must provide 
written informed consent. The Investigator will then determine the potential patient’s suitability 
for the study by interviewing the patient and by performing per-protocol Screening assessments. 
Pre-randomization Approval by Tonix Pharmaceuticals will be required prior to Visit 2 in 
addition to satisfying all other eligibility and randomization criteria. If excluded medications are 
to be withdrawn for the explicit purpose of participation in this study, the patient must have 
already provided consent and signed an ICF before the withdrawal or down-titration of any 
medication is initiated. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug Packaging, 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-CY-PA201, Sponsor name and address, bottle number, quantity, storage 
conditions, usage instructions, and caution statements for investigational new drug, ie, 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 40 tablets. One bottle will be dispensed to each patient at 
Visit 2 (Baseline), and then 2 bottles will be dispensed at Visit 3 (Week 2), Visit 4 (Week 6), and 
Visit 5 (Week 10). This will provide the patient with enough tablets to cover the 2 or 4 weeks of 
dosing between visits, plus additional tablets to cover loss and/or visit window variability. The 
patient should be instructed to take all the tablets in one bottle before opening the second bottle. 
The patient should be instructed to keep this study drug in a safe location out of extreme 
environmental conditions and out of the reach of children and pets, and be instructed that this 
drug is not to be taken by any individual other than the study patient. Each patient will also be 
instructed that they are expected to return both bottles (even if empty) 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 site should be under locked and secure conditions 
with limited staff access. Study drug should be stored at 20−25°C/68−77°F in a 
temperature/humidity-monitored room; however, additional details on acceptable brief 
excursions and other pertinent information will be provided to the site.  
10.2. 
Dosing Instructions 
Patients will be instructed to take 1 tablet of randomly assigned study drug TNX-102 SL 2.8 mg 
or placebo tablet sublingually (under the tongue) each evening at bedtime starting at bedtime on 
Day 1 (Day of Visit 2) and continuing through Day 14. At the Week 2 Visit, patients will be 
instructed to increase the dose to 2 tablets at bedtime, administered simultaneously and under the 
tongue beginning on Day 15 and continuing through the end of the study.   
The study drug should be taken at bedtime after teeth brushing and other oral care has been 
completed. The mouth/sublingual area should be moist at the time of dosing, so the patient 
should drink a few sips of water prior to dosing, especially if prone to dry mouth. Patients will be 
instructed to place the 1 or 2 SL tablets under their tongue (if 2, placed simultaneously under 
tongue) and keep them there until they have dissolved (approximately 90 seconds). They should 
not swallow, crush, or chew the tablets. Patients should not eat, drink, or chew gum for at least 
15 minutes after dosing, and preferably not drink any hot, cold, or acidic beverage until morning. 
Patients also should not talk for at least 5 minutes after placing the study drug in the mouth 
(under the tongue). Patients will be reminded that only 2 tablets are allowed per day. Note: If the 
patient misses a dose, instruct the patient to continue dosing with 2 tablets the next evening; ie, 
they should not take more to make up for the missed dose. 
If the patient reports intolerable side effects that are likely to result in premature discontinuation 
from the study, then the dose of study drug may be reduced to 1 tablet sublingually nightly, with 


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Medical Monitor approval. Any reduction in study drug dose must be documented in the case 
report form (CRF). The goal is for the patient to be on a stable and final dose of study drug 
starting from the Week 2 Visit, at the highest dose tolerated (preferably 2 tablets daily at 
bedtime). It is anticipated that only a few patients will require dosage reduction, as TNX-102 SL 
5.6 mg has been well-tolerated in previous Phase 3 studies of TNX-102 SL. Moreover, the 
gradual titration from 1 tablet for the first 2 weeks to 2 tablets for the remainder of the study 
should help with acclimation to the higher dose.  
10.3. 
Dispensing Instructions 
Each patient who has met the randomization criteria (Section 8.4) will be assigned a double-
blind treatment bottle at Visit 2 via the Interactive Response Technology (IRT), with a unique, 
but otherwise random bottle number that is generated when the study coordinator successfully 
completes randomization procedures. Patients will take one sublingual tablet each evening at 
bedtime for the first 2 weeks. 
Beginning with the evening of the Week 2 Visit, patients will take 2 sublingual tablets each 
evening at bedtime, and will continue doing so throughout the course of the study. Only in the 
event of AEs that might possibly lead to discontinuation can the patient reduce the dose to 1 
tablet per evening, with approval of the Principal Investigator and Medical Monitor. 
 
Study treatments at maximum dosage for the double-blind treatment phase are either: 
 
Treatment A: 2  TNX-102 SL 2.8 mg tablets (“TNX-102 SL”) to be taken 
sublingually (simultaneously) once daily at bedtime. 
Treatment B: 2  placebo tablet (“placebo”) to be taken sublingually (simultaneously) 
once daily at bedtime. 
 
In the event that a study drug bottle is lost, a new bottle will be provided by the IRT when 
appropriately requested by the site and/or the Sponsor or designee. 
10.4. 
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. 
10.5. 
Study Drug Accountability and Reconciliation 
All patients will be expected to bring their bottles of study drug with them to all study visits 
(including empty bottles). At each study visit, the site staff will inspect the drug bottles and 
perform a count of the tablets 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 bottles. If it is found that the 
patient is not taking the study drug as expected, the patient will be re-counseled with 
instructions, and this should be noted in the patients’ records. A deviation should be recorded on 


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any patient who is less than 70% compliant with dosing between visits, and a Medical Monitor 
should be contacted. In addition, if a patient fails to return >8 tablets within a 4-week (or >4 in a 
2-week period), the PI is required to assess the patient for any potential drug abuse, misuse, or 
diversion. This assessment should be documented and reported within the Drug Accountability 
case report form. 
Tonix or its designee will perform drug accountability, which entails reconciliation between the 
amount of drug shipped to the study site, study drug assigned and dispensed to the patient 
(including returned unused assigned study drug), and study supplies that were never dispensed 
and/or assigned to patients. 


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11. 
STUDY VISITS 
The overall and detailed schedule for study procedures and visits is provided in Table 2.  
11.1. 
Visit 1 (Screening Visit: Day -35 to Day -7) 
11.1.1. 
Informed Consent 
Before the potential patient has undergone any study-related screening procedures, including any 
down-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 the 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. The patient will be 
required to sign all updated ICFs. 
11.1.2. 
Screening Overview 
The first study visit, Screening Visit 1, will be when the study is thoroughly explained to the 
prospective patient, when written informed consent will be obtained and documented, and when 
certain protocol-specified study procedures and assessments will be completed. Screening Visit 1 
will start a variable length Screening and Washout Period. The length of the Screening and 
Washout Period is to be no shorter than 7 days (since the “run-in” period during which baseline 
diary data are collected must be at least 7 days in duration), but may be as long as 35 days in 
order to accommodate medication washout or other study requirements. For extenuating 
circumstances, the total duration of the Screening period may be increased to up to a maximum 
of 49 days with Medical Monitor approval.  
If the patient does not need to complete any medication washout, and assuming all screening 
procedures have been successfully completed and initial eligibility has been confirmed, then the 
patient may begin the 7-day run-in period as soon as the Screening Visit has been completed. 
Yet, due to potential delays in the issuance of a final laboratory report (eg, when a confirmatory 
analysis is required, typically on a urine drug screen analyte that is preliminarily positive), it is 
recommended that the Baseline Visit is scheduled at least 10 days from the Screening Visit. If 
the patient needs to complete medication washout prior to the start of the run-in period, the 
down-titration schedule for the patient and the date on which the patient should start the run-in 
period should be provided in writing to the patient. It is acceptable if another clinic visit is 
deemed necessary by the Investigator before initiating the run-in period (and should be recorded 
as an Unscheduled Visit). It is important to remember that any patient with a positive urine drug 
screen (UDS) (for a drug requiring washout) must return to the site for a repeat UDS prior to 
beginning their 7-day baseline data collection period. The repeat UDS for benzodiazepines must 
be centrally analyzed; all others may be performed on site. Patients who test positive for 
cannabis/THC at the Screening Visit but are deemed eligible to continue are not required to 
undergo repeat UDS testing.  


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11.1.3. 
Patient Numbering 
All screened patients will be assigned a unique patient number. 
11.1.4. 
Screening Assessments and Procedures 
The following Screening assessments/procedures will be completed in the following general 
order: 
• Obtain written informed consent to participate 
• Check inclusion/exclusion criteria 
• Collect demographics information 
• Collect medical history 
• Confirmation of prior SARS-CoV-2 infection 
• Perform WHO COVID-19 severity classification 
• Collect information on prior/concomitant medication 
• Perform complete physical examination, including measurement of height and 
weight, and calculation of BMI 
• Thorough examination of the oral cavity. This examination should include a careful 
visual examination of the sublingual area, tongue, buccal mucosa, lips, palate, and 
gums, aided with a tongue depressor, as well as palpation of the lips, hard palate, and 
floor of the mouth. Any abnormalities should be noted on the oral cavity examination 
source document. 
• Administer Screening Visit Version of the mMBM  
• Administer Mini International Psychiatric Interview 7.0.2 – Modules A (Major 
Depressive Episode), C (Manic and Hypomanic Disorders), I (Alcohol Use Disorder), 
J (Substance Use Disorder), K (Psychotic Disorders), and O (Rule Out Medical, 
Organic, or Drug Causes for All Disorders). 
• Administer McLean Screening Instrument for Borderline Personality Disorder 
(MSI-BPD) 
• Administer “Baseline/Screening” version of the Columbia-Suicide Severity Rating 
Scale (C-SSRS). Any patient with C-SSRS Type 3, 4, or 5 ideation during the 
preceding 6 months or any suicidal behavior during the preceding 1 year should be 
screen-failed 
• Patient should complete the following patient-reported outcomes (PROs): 
a. NRS assessment of 7-day recall of average daily Long COVID pain. Patients 
should only continue screening if they score ≥ 4 and ≤ 9. 
b. PCFS scale 
• Clinical laboratory tests, including serum chemistry, hematology, urinalysis, 


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•  Viral laboratory tests, including serology for HIV, hepatitis B virus, and hepatitis C 
virus (HCV) 
• Urine drug screening 
• Serum pregnancy test for females of child-bearing potential (processed by central lab)  
• Vital signs 
• 12-lead electrocardiogram 
• Only those patients meeting all of the inclusion and none of the exclusion criteria will 
be eligible to continue. Eligible patients will: 
a. Be asked to complete accurate pain reporting and placebo response reduction 
training. 
b. Be trained on the eDiary and instructed regarding the questions that will be 
asked of them. They will also receive information and materials necessary to 
initiate their daily diary record, along with information of what they are to do 
if they have difficulties recording their information. Patients will be asked to 
start the diary that evening. Due to limitations in the reporting window, 
patients who are planning on international travel during the study period or 
who work night shifts should not be considered for the study. 
c. Receive an appointment to return to the clinic for Visit 2. 
d. Receive a schedule for down-titration (if required) of any prohibited 
medications to be discontinued. 
Pre-randomization Approval by Tonix Pharmaceutics will be required prior to Visit 2 in addition 
to satisfying all other eligibility and randomization criteria.  
11.2. 
Visit 2 (Baseline: Day 1) 
Visit 2 should be scheduled after the patient has completed their medication washout and 
completed at least 7 days of diary data entries. If the patient meets randomization criteria, the 
patient will be authorized to continue in the study. The patient will be randomized via the 
randomization system to receive double-blind study drug.  
If the patient does not satisfy randomization criteria, the patient has failed to qualify for this 
study and should be considered a screen failure, with the reason documented. There is no 
requirement for a follow-up visit for screen failures. 
11.2.1. 
Randomization Criteria 
Only patients meeting all of the following randomization criteria will be eligible for 
randomization: 
1. Continues to meet all inclusion and exclusion criteria, including urine and blood test results 
and is successfully and consistently utilizing the diary system. 
2. Patient’s pain satisfies the following criteria, as assessed by diary pain scores (24-hour 
recall): 


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a. A mean Long COVID pain intensity score ≥ 4 and ≤ 9 on the 11-point (0−10) NRS 
scale for the 7 days immediately preceding Visit 2; and 
b. No more than 2 individual days with a Long COVID pain score < 4 on the 7 days 
immediately preceding Visit 2; and 
c. No score of 10 on any of the 7 days immediately preceding Visit 2, and 
d. Long COVID pain scores recorded on at least 5 out of the 7 days immediately 
preceding Visit 2. 
11.2.2. 
Baseline Visit 
For patients who have qualified for randomization, these assessments and procedures will be 
completed in the following general order: 
• Collect any new medical history information 
• Record any additional prior and concomitant medication use 
• Targeted physical exam, focusing on previous and new findings and AEs  
• Oral cavity examination. This examination should include a careful visual 
examination of the sublingual area, tongue, buccal mucosa, lips, palate, and gums. 
Any abnormalities should be noted on the oral exam source document. It is 
recommended that both non-significant as well as significant findings be noted so that 
there is a complete and accurate baseline assessment available for comparison to 
findings at later visits. 
• Administer Baseline/Post-Randomization Version of the mMBM 
• Administer the “Since Last Visit” version of the C-SSRS. Any patient exhibiting 
Type 3, 4, or 5 suicidal ideation or any suicidal behavior since the Screening Visit 
should be screen-failed and assessed for appropriate follow-up care. 
• Patient should complete the following PROs: 
a. SDS 
b. PROMIS Short Form – Sleep Disturbance 
c. PROMIS Short Form v1.0 – Fatigue 8a  
d. PROMIS Short Form v1.0 – Cognitive Function - Abilities  
e. PCFS 
f. ISI 
g. ESS 
• Administer urine pregnancy test for females of child-bearing potential (processed in-
clinic) 
• Vital signs 


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• Once it has been confirmed that the patient remains eligible, randomize patient via 
IRT Randomization System 
• Assessment of eDiary compliance of 24-hour recall of worst Long COVID pain and 
sleep quality  
• Assess occurrence of AEs 
• Dispense bottle of double-blind study drug as assigned via the IRT 
• Review patient instructions regarding study drug dosing and assess drug compliance 
(Section 10.2 and Section 12.1.8). 
• Patients should complete the training on accurate pain reporting and placebo response 
reduction training as required. 
• Optional blood draw for pharmacogenomics (after the separate ICF has been signed 
for the pharmacogenomic substudy) – It is preferred that the draw is done at the 
Baseline Visit (Visit 2); however, it can be drawn at a future visit. 
11.2.3. 
Study Drug Dispensing 
Qualified patients will be assigned a treatment bottle number via the randomization system 
(Section 10.3). The treatment bottle numbers are random and unique and will not necessarily be 
dispensed in any particular order. The treatment bottle number will be recorded in the patient’s 
records. 
11.2.4. 
Patient Instructions 
After all assessments have been completed and before leaving the clinic at Visit 2, patients 
should: 
• Be dispensed a single unopened bottle of double-blind study drug. The patient should 
be instructed to begin dosing with study drug at bedtime, starting the night of Visit 2. 
• Receive instruction regarding proper sublingual dosing technique and the time of 
expected dosing. 
• Receive reinforcement about the importance of completing all questions that will be 
asked on the daily diary and receive re-instruction, if necessary, on what they are to 
do if they have difficulties recording their information. NOTE: Patients should be 
instructed that they should complete their diary within the required time window. 
• Receive an appointment for Visit 3. 
• The patient should be instructed to call the site if they develop a lesion under the 
tongue or any other localized AE in the oral cavity thought potentially related to study 
drug exposure, specifically to determine if an Unscheduled Visit for an oral cavity 
examination is necessary prior to the next scheduled visit. Reports of oral numbness, 
tingling, or noticeable taste (eg, bitter, metallic, unpleasant) after dosing do not 
require unscheduled examinations.  


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11.3. 
Visit 3 (Week 2) 
Visit 3 should occur after 2 weeks of treatment, on Day 15 -4 / +7 days. For those patients unable 
to return to the site (ie, extenuating circumstances due to COVID-19 pandemic), a telephone visit 
is an option.  
The following assessments and procedures are scheduled for this visit in the following general 
order: 
• Record concomitant medication use 
• Examination of the oral cavity. Ensure that this exam includes the sublingual area and 
that any abnormalities are carefully described on the oral exam source document. 
(Telephone visit exception – visual exam of the oral cavity is not required – but in 
addition to standard inquiry about AEs, site staff will inquire specifically if there have 
been any changes or problems in the oral cavity. Patients reporting any concerning 
lesion description or painful processes in the oral cavity possibly related to study drug 
exposure should be strongly urged to come into the clinic for an Unscheduled Visit 
for oral cavity exam. In circumstances in which, due to the COVID-19 pandemic, it is 
not possible for the patient to return to the clinic for the Unscheduled Visit exam, a 
clinician certified by the Sponsor to conduct oral cavity examination should contact 
the patient by phone and obtain greater history and description of the oral cavity AE 
by patient, potentially augmented with images of oral cavity taken by the patient and 
sent to the site for the examining clinician to textually document in the oral exam 
source document. In such cases in which the patient is unwilling or unable to come in, 
Principal Investigator (PI) and Medical Monitor should also confer on whether study 
drug should be discontinued.)  
• Administer Baseline/Post-Randomization Version of the mMBM  
• Administer the “Since Last Visit” version of the C-SSRS. (Telephone visit exception: 
C-SSRS is administered over the phone) 
• Patient should complete the following PROs (Telephone visit exception: all PROs 
should be mailed ahead of the visit and returned to the clinic after completion via 
courier): 
a. SDS 
b. PROMIS Short Form – Sleep Disturbance 
c. PROMIS Short Form v1.0 – Fatigue 8a  
d. PROMIS Short Form v1.0 – Cognitive Function - Abilities  
e. PGI-C 
f. ESS 
• Administer urine pregnancy test for females of child-bearing potential (processed in-
clinic). (Telephone visit exception: urine pregnancy test will be performed at home by 
patient for women of child-bearing potential). 


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• Record vital signs. (Telephone visit exception: vital signs are not required). 
• Assessment of eDiary compliance of 24-hour recall of worst Long COVID pain and 
sleep quality. Discuss any compliance concerns with the patient and provide re-
training as needed. 
• Patients should complete the training on accurate pain reporting and placebo response 
reduction training as required. 
• Assess study drug compliance and collect previously dispensed study drug and bottle. 
(Telephone visit exception: patient will be instructed to count the number of tablets 
remaining in their current bottle[s], document this on a patient provided form, and 
return this form with the study drug [including bottle(s)] to the site for assessment of 
compliance in a pre-paid pre-addressed courier envelope supplied in a “tele-visit” 
package to patient). 
• Assess occurrence of AEs 
• Discuss the scheduled increase in dose of study drug from 1 sublingual tablet 
(Days 1−14) to 2 tablets administered sublingually and simultaneously at bedtime 
throughout the remainder of the study (Days 15−99). Remind patient to contact the 
site for any issues regarding tolerability and to only make changes in dose under the 
direction of the Investigator. 
• Dispense new bottles (unopened) of double-blind study drug as assigned by IRT. 
Patients should begin dosing from new study drug bottles on the evening of the visit. 
(Telephone visit exception: study drug will be mailed to the patient via courier. 
Patients should begin dosing from new study drug bottles on the evening of the visit). 
• Confirm that the increase in drug dosing to 2 tablets sublingually at bedtime is 
understood by patient. 
• Optional blood draw for pharmacogenomics (after the separate ICF has been signed 
for pharmacogenomic substudy) - if not drawn already at a prior visit 
After all of the assessments at each visit have been completed, the patient should be given an 
appointment to return to the clinic for the next scheduled visit, and be re-instructed, as necessary, 
in the completion of the diary, dosing instructions, and reminded to bring all study drug (and 
bottles) back to the clinic at their next visit.  
11.4. 
Visit 4 (Week 6) 
Visit 4 should occur after 6 weeks of treatment, on Day 43 ± 7 days. For those patients unable to 
return to the site (ie, extenuating circumstances due to COVID-19 pandemic), a telephone visit is 
an option.  
The following assessments and procedures are scheduled for this visit in the following general 
order: 
• Record concomitant medication use 


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• Oral cavity examination. Ensure that this exam includes the sublingual area and that 
any abnormalities are carefully described on the oral exam source document. 
(Telephone visit exception: visual exam of the oral cavity is not required – but in 
addition to standard inquiry about AEs, site staff will inquire specifically if there have 
been any changes or problems in the oral cavity. Patients reporting any concerning 
lesion description or painful processes in the oral cavity possibly related to study drug 
exposure should be strongly urged to come into the clinic for an Unscheduled Visit 
for oral cavity exam. In circumstances in which, due to the COVID-19 pandemic, it is 
not possible for the patient to return to the clinic for the Unscheduled Visit exam, a 
clinician certified by the Sponsor to conduct oral cavity examination should contact 
the patient by phone and obtain greater history and description of the oral cavity AE 
by patient, potentially augmented with images of oral cavity taken by the patient and 
sent to the site for the examining clinician to textually document in the oral exam 
source document. In such cases in which the patient is unwilling or unable to come in, 
PI and Medical Monitor should also confer on whether study drug should be 
discontinued.)  
• Administer Baseline/Post-Randomization Version of the mMBM 
• Administer the “Since Last Visit” version of the C-SSRS. (Telephone visit exception: 
C-SSRS is administered over the phone) 
• Patient should complete the following PROs (Telephone visit exception: all PROs 
should be mailed ahead of the visit and returned to the clinic after completion via 
courier): 
a. SDS 
b. PROMIS Short Form – Sleep Disturbance 
c. PROMIS Short Form v1.0 – Fatigue 8a  
d. PROMIS Short Form v1.0 – Cognitive Function - Abilities  
e. PGI-C 
f. ESS 
• Clinical laboratory tests, including serum chemistry, hematology, urinalysis 
• Administer urine pregnancy test for females of child-bearing potential (processed in-
clinic). (Telephone visit exception: urine pregnancy test will be performed at home by 
patient for women of child-bearing potential). 
• Record vital signs. (Telephone visit exception – vital signs are not required) 
• Assessment of eDiary compliance of 24-hour recall of worst Long COVID pain and 
sleep quality Discuss any compliance concerns with the patient and provide retraining 
as needed. 
• Patients should complete the training on accurate pain reporting and placebo response 
reduction training as required. 


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• Assess study drug compliance and collect previously dispensed study drug and bottle. 
(Telephone visit exception: patient will be instructed to count the number of tablets 
remaining in their current bottle[s], document this on a patient provided form, and 
return this form with the study drug [including bottle(s)] to the site for assessment of 
compliance in a pre-paid pre-addressed courier envelope supplied in a “tele-visit” 
package to patient). 
• Assess occurrence of AEs 
• Dispense new bottles (unopened) of double-blind study drug as assigned by IRT. 
Patients should begin dosing from new study drug bottles on the evening of the visit. 
(Telephone visit exception: study drug will be mailed to the patient via courier. 
Patients should begin dosing from new study drug bottles on the evening of the visit). 
• Optional blood draw for pharmacogenomics (after the separate ICF has been signed 
for the pharmacogenomic substudy) - if not drawn already at a prior visit. 
After all of the assessments at each visit have been completed, the patient should be given an 
appointment to return to the clinic for the next scheduled visit, and be re-instructed, as necessary, 
in the completion of the diary, dosing instructions, and reminded to bring all study drug (and 
bottles) back to the clinic at their next visit.  
11.5. 
Visit 5 (Week 10) 
Visit 4 should occur after 6 weeks of treatment, on Day 71 ± 7 days. For those patients unable to 
return to the site (ie, extenuating circumstances due to COVID-19 pandemic), a telephone visit is 
an option.  
The following assessments and procedures are scheduled for this visit in the following general 
order: 
• Record concomitant medication use 
• Oral cavity examination. Ensure that this exam includes the sublingual area and that 
any abnormalities are carefully described on the oral exam source document. 
(Telephone visit exception: visual exam of the oral cavity is not required – but in 
addition to standard inquiry about AEs, site staff will inquire specifically if there have 
been any changes or problems in the oral cavity. Patients reporting any concerning 
lesion description or painful processes in the oral cavity possibly related to study drug 
exposure should be strongly urged to come into the clinic for an Unscheduled Visit 
for oral cavity exam. In circumstances in which, due to the COVID-19 pandemic, it is 
not possible for the patient to return to the clinic for the Unscheduled Visit exam, a 
clinician certified by the Sponsor to conduct oral cavity examination should contact 
the patient by phone and obtain greater history and description of the oral cavity AE 
by patient, potentially augmented with images of oral cavity taken by the patient and 
sent to the site for the examining clinician to textually document in the oral exam 
source document. In such cases in which the patient is unwilling or unable to come in, 
PI and Medical Monitor should also confer on whether study drug should be 
discontinued.) 


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• Administer Baseline/Post-Randomization Version of the mMBM  
• Administer the “Since Last Visit” version of the C-SSRS. (Telephone visit exception: 
C-SSRS is administered over the phone).  
• Patient should complete the following PROs (Telephone visit exception: all PROs 
should be mailed ahead of the visit and returned to the clinic after completion via 
courier): 
a. SDS 
b. PROMIS Short Form – Sleep Disturbance 
c. PROMIS Short Form v1.0 – Fatigue 8a  
d. PROMIS Short Form v1.0 – Cognitive Function - Abilities  
e. PGI-C 
f. ESS 
• Administer urine pregnancy test for females of child-bearing potential (processed in-
clinic). (Telephone visit exception: urine pregnancy test will be performed at home by 
patient for women of child-bearing potential). 
• Record vital signs. (Telephone visit exception: vital signs are not required) 
• Assessment of eDiary compliance of 24-hour recall of worst Long COVID pain and 
sleep quality. Discuss any compliance concerns with the patient and provide re-
training as needed. 
• Patients should complete the training on accurate pain reporting and placebo response 
reduction training as required. 
• Assess study drug compliance and collect previously dispensed study drug and bottle. 
(Telephone visit exception: patient will be instructed to count the number of tablets 
remaining in their current bottles, document this on a patient provided form, and 
return this form with the study drug [including bottles] to the site for assessment of 
compliance in a pre-paid pre-addressed courier envelope supplied in a “tele-visit” 
package to patient).  
• Assess occurrence of AEs 
• Dispense new bottles (unopened) of double-blind study drug as assigned by IRT. 
Patients should begin dosing from new study drug bottles on the evening of the visit. 
(Telephone visit exception: study drug will be mailed to the patient via courier. 
Patients should begin dosing from new study drug bottles on the evening of the visit). 
• Review patient instructions regarding diary completion. 
• Optional blood draw for pharmacogenomics (after the separate ICF has been signed 
for the pharmacogenomic substudy) - if not drawn already at a prior visit. 
After all of the assessments at each visit have been completed, the patient should be given an 
appointment to return to the clinic for the next scheduled visit, and be re-instructed, as necessary, 


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in the completion of the diary, dosing instructions, and reminded to bring all study drug (and 
bottles) back to the clinic at their next visit.  
11.6. 
Visit 6 (Week 14 or Early Termination) 
11.6.1. 
Visit 6 (Week 14) 
Visit 6 should occur after 14 weeks of double-blind study drug treatment, scheduled at Day 99  
-4 / +7 days. At this visit, the patient will return all study drug and be instructed that there is no 
longer any need to complete the diary. If circumstances involving the COVID-19 have resulted 
in the patient being reluctant to attend this visit at the clinic, it should be strongly emphasized 
that a complete safety assessment at end of study necessitates the in-person visit. If the patient 
absolutely refuses or it is impossible to attend the clinic because of a COVID-19 pandemic-
related “stay at home” order or similar, the PI should discuss the case with the Medical Monitor. 
Approval for a Week 14 telephone visit may be granted by the Medical Monitors on a case by 
case basis. In cases in which it is feasible for a site’s own research staff, with or without a 
research clinician, to make a home visit for Week 14/Visit 6 (or ET), a home visit should be 
conducted rather than a telephone visit in order to collect greater safety data than the telephone 
visits allow. Home visits may be conducted by any qualified staff member and will allow, in 
addition to all procedures conducted in a telephone visit, collection of vital signs and weight, and 
venipuncture for Week 14/ET laboratory tests and, for women of child-bearing potential, 
collection of urine specimen for pregnancy test upon return to site. Home visits that include a 
clinician certified by Sponsor to conduct the oral cavity exam will additionally be able to include 
an oral cavity examination and a brief physical examination, allowing completion of all 
Week 14/ET safety assessments. 
The following assessments and procedures are scheduled for this visit in the following general 
order: 
• Record concomitant medication use 
• Perform brief physical examination, including measurement of weight and calculation 
of BMI (Telephone visit exception: brief physical exam is not required). 
• Oral cavity examination. Ensure that this exam includes the sublingual area and that 
any abnormalities are carefully described on the oral exam source document. 
(Telephone visit exception: visual exam of the oral cavity is not required – but in 
addition to standard inquiry about AEs, site staff will inquire specifically if there have 
been any changes or problems in the oral cavity. Patients reporting any concerning 
lesion description or painful processes in the oral cavity possibly related to study drug 
exposure should be strongly urged to come into the clinic for an Unscheduled Visit 
for oral cavity exam. In circumstances in which, due to the COVID-19 pandemic, it is 
not possible for the patient to return to the clinic for the Unscheduled Visit exam, a 
clinician certified by the Sponsor to conduct oral cavity examination should contact 
the patient by phone and obtain greater history and description of the oral cavity AE 
by patient, potentially augmented with images of oral cavity taken by the patient and 
sent to the site for the examining clinician to textually document in the oral exam 
source document.) 


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• Administer Baseline/Post-Randomization Version of mMBM 
• Administer the “Since Last Visit” version of the C-SSRS. (Telephone visit exception: 
C-SSRS is administered over the phone). 
• Patient should complete the following PROs (Telephone visit exception: all PROs 
should be mailed ahead of the visit and returned to the clinic after completion via 
courier): 
a. SDS 
b. PROMIS Short Form – Sleep Disturbance 
c. PROMIS Short Form v1.0 – Fatigue 8a  
d. PROMIS Short Form v1.0 – Cognitive Function - Abilities  
e. PGI-C 
f. PCFS 
g. ISI 
h. ESS 
• Clinical laboratory tests, including serum chemistry, hematology, urinalysis. 
(Telephone visit exception: laboratory tests are not required). 
• Administer urine pregnancy test for females of child-bearing potential (processed 
in-clinic). (Telephone visit exception: urine pregnancy test will be performed at home 
by patient for women of child-bearing potential). 
• Record vital signs (Telephone visit exception: vital signs are not required). 
• Assessment of eDiary compliance of 24-hour recall of worst Long COVID pain and 
sleep quality. Discuss any compliance concerns with the patient and provide re-
training as needed. 
• Assess study drug compliance and collect previously dispensed study drug and bottle. 
(Telephone visit exception: patient will be instructed to count the number of tablets 
remaining in their current bottles, document this on a patient provided form, and 
return this form with the study drug [including bottles] to the site for assessment of 
compliance in a pre-paid pre-addressed courier envelope supplied in a “tele-visit” 
package to patient). 
• Assess occurrence of AEs. 
• Optional blood draw for pharmacogenomics (after the separate ICF has been signed 
for the pharmacogenomic substudy) - if not already drawn at a prior visit. 
11.6.2. 
Early Termination (Post-Randomization) 
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 


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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 data or place the patient at risk 
• The request of the patient, Investigator, or Tonix, whether for administrative or other 
reasons 
• Pregnancy 
Patients who wish to terminate their participation in the study should be instructed to come to the 
clinic for an ET 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 
and bottles. NOTE: These visit procedures are not intended for patients who fail to qualify for 
randomization or for patients who withdraw from the study prior to receipt of a dose of double-
blind study drug. 
The following assessments and procedures are completed at this visit as ordered below: 
• Document reason for early termination 
• Perform brief physical examination, including weight and BMI (Telephone visit 
exception: brief physical exam is not required) 
• Record concomitant medication use 
• Oral cavity examination. Ensure that this exam includes the sublingual area and that 
any abnormalities are carefully described on the oral exam source document. 
(Telephone visit exception: visual exam of the oral cavity is not required – but in 
addition to standard inquiry about AEs, site staff will inquire specifically if there have 
been any changes or problems in the oral cavity. Patients reporting any concerning 
lesion description or painful processes in the oral cavity possibly related to study drug 
exposure should be strongly urged to come into the clinic for an unscheduled visit for 
oral cavity exam). In circumstances in which, due to the COVID-19 pandemic, it is 
not possible for the patient to return to the clinic for the Unscheduled Visit exam, a 
clinician certified by the Sponsor to conduct oral cavity examination should contact 
the patient by phone and obtain greater history and description of the oral cavity AE 
by patient, potentially augmented with images of oral cavity taken by the patient and 
sent to the site for the examining clinician to textually document in the oral exam 
source document.) 
• Administer Baseline/Post-Randomization Version of the mMBM  
• Administer the “Since Last Visit” version of the C-SSRS (Telephone visit exception: 
C-SSRS is administered over the phone). 


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• Have the patient complete all PROs: (Telephone visit exception: all PROs should be 
mailed ahead of the visit and returned to the clinic after completion via courier): 
a. SDS 
b. PROMIS Short Form – Sleep Disturbance 
c. PROMIS Short Form v1.0 – Fatigue 8a  
d. PROMIS Short Form v1.0 – Cognitive Function - Abilities  
e. PGI-C 
f. PCFS 
g. ISI 
h. ESS 
• Clinical laboratory tests, including serum chemistry, hematology, urinalysis. 
(Telephone visit exception: laboratory tests are not required). 
• Administer urine pregnancy test for females of child-bearing potential (processed in-
clinic). (Telephone visit exception: urine pregnancy test will be performed at home by 
patient for women of child-bearing potential). 
• Record vital signs (Telephone visit exception: vital signs are not required). 
• Assessment of eDiary compliance of 24-hour recall of worst Long COVID pain and 
sleep quality. Discuss any compliance concerns with the patient and provide re-
training as needed. Assess study drug compliance and collect previously dispensed 
study drug and bottle. (Telephone visit exception: patient will be instructed to count 
the number of tablets remaining in their current bottles, document this on a patient 
provided form, and return this form with the study drug [including bottles] to the site 
for assessment of compliance in a pre-paid pre-addressed courier envelope supplied 
in a “tele-visit” package to patient). 
• Assess occurrence of AEs. 
• Optional blood draw for pharmacogenomics (after the separate ICF has been signed 
for the pharmacogenomic substudy) - if not already drawn at a prior visit. 
Once these assessments have been completed, the patient may be discharged from the study, 
provided that there is no need for additional follow-up to continue to monitor an AE or other 
condition. All participants will receive two safety follow-up phone calls approximately 2 and 
4 weeks later (Visits 7 and 8). 
11.7. 
Visit 7 (Week 16/Post-study Safety Follow-up) 
Visit 7 should occur approximately 2 weeks ± 7 days after Visit 6/ET. This visit will be 
performed by telephone, to collect any additional data on concomitant medication and AEs and 
the general condition of the patient.  


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11.8. 
Visit 8 (Week 18/1-Month Post-study Safety Follow-up) 
Visit 8 should occur approximately 4 weeks ± 7 days after Visit 6/ET. This visit will be 
performed by telephone, to collect any additional data on concomitant medication and AEs and 
the general condition of the patient.  
11.9. 
Unscheduled Visit 
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, physician 
examination, or other findings. If an additional study visit is warranted, or occurs, the date and 
nature of the visit will be documented in the CRF and in the source documents. 
Patients should contact the investigative site as soon as possible if they experience a lesion under 
the tongue or any other oral cavity AE potentially related to study drug exposure (other than 
transient numbness, tingling, or bitter/metallic/unpleasant taste after dosing), specifically to 
determine if they should return to the clinic for an unscheduled oral cavity examination.   
Note: If an AE is ongoing at the time of the Week 14/ET visit or there is suspicion that an AE 
has occurred due to the drug even after discontinuation, the patient may be brought in for an 
unscheduled in-person visit for additional follow-up. 


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12. 
STUDY ASSESSMENTS 
The primary efficacy endpoint and many of the secondary and exploratory efficacy endpoints in 
this study are derived from patient-completed assessments. Therefore, it is critical that these 
assessments are conducted in the specified order, according to specific instructions, and in a 
setting where the patient has minimal distractions and sufficient time to complete them. After 
completion of these assessments, the study coordinator, unless specifically prohibited by 
instrument instructions, should review the responses for completeness with the patient. 
12.1. 
Efficacy Assessments 
12.1.1. 
Modified Michigan Body Map  
The MBM is based on the 2011 FM Survey Criteria, a tool that is commonly used to assess for 
the presence of multi-site pain in FM, a disorder characterized by widespread body pain, along 
with comorbid symptomatology similar to that experienced by patients with Long COVID. The 
2011 FM Survey Criteria include the assessment of pain in 19 specific body areas using the 
Widespread Pain Index (WPI). The areas from the WPI are then combined with the Symptom 
Severity scale to assess the presence and severity of FM (Wolfe et al. 2010; Wolfe et al. 2011). 
The MBM is a graphic mannequin with the 19 areas from the WPI superimposed upon it in 
anatomically relevant locations. The MBM also contains 16 additional areas for more general 
use. The MBM, and its online version, have been validated in patients with chronic pain 
(Brummett et al. 2016; Hassett et al. 2019).  
Tonix Pharmaceuticals has modified the MBM (mMBM) in consultation with its authors. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
12.1.2. 
Sheehan Disability Scale (SDS) 
SDS is a brief self-reporting tool that rates the extent to which work/school, social life, and home 
life or family responsibilities are impaired by the symptoms on a 10-point visual analog scale 
(Williams et al. 2000; Appendix 6). The 3 items can also be summed into a single dimensional 
measure of global functional impairment that ranges from 0 (unimpaired) to 30 (highly 
impaired). SDS will be administered as shown in Table 2. 
12.1.3. 
PROMIS Scales 
PROMIS is the Patient-Reported Outcome Measurement Information System 
(www.nihpromis.org), an NIH-funded initiative to develop instruments to be used across chronic 
conditions. 
Three PROMIS Scales will be assessed in this study, including the Sleep Disturbance scale 
(version 8a) (Appendix 7), the Fatigue scale (version 8a) (Appendix 8,) and the Cognitive 
Function – Abilities scale (version 8a) (Appendix 9). Each of these scales will be assessed as 
shown in Table 2. 


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12.1.4. 
Patient Global Impression of Change (PGI-C) 
The PGI-C is a validated instrument to gauge the patient’s assessment of change in condition 
(Guy. 1976; Dworkin et al. 2008;  
 


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Appendix 10). This form will be completed by the patient at time points shown in Table 2. 
12.1.5. 
Post-COVID-19 Functional Status (PCFS) scale 
PCFS scale is an ordinal scale for assessment of patient-relevant functional limitations over time 
after COVID-19 infection (Klok et al 2020; Machado et al 2021; available at 
https://osf.io/qgpdv/; Appendix 4). The PCFS scale will be administered as shown in Table 2. 
12.1.6. 
Insomnia Severity Index (ISI) – Patient version 
The ISI is a 7-item self-reported questionnaire assessing the nature, severity, and impact of 
insomnia (Spielman et al. 1987; Morin et al, 2011; Appendix 11). 
The usual recall period is the “last month” and the dimensions evaluated are severity of sleep 
onset, sleep maintenance and early morning awakening problems, sleep dissatisfaction, 
interference of sleep difficulties with daytime functioning, noticeability of sleep problems by 
others, and distress caused by the sleep difficulties. The ISI questionnaire will be administered as 
shown in Table 2. 
The scores range from 0 (no problem) to 4 (very severe problem) yielding a total score ranging 
from 0 to 28. The total score is interpreted as: 
0–7 = absence of insomnia 
8–14 = sub-threshold insomnia 
15–21 = moderate insomnia 
22–28 = severe insomnia 
12.1.7. 
Epworth Sleepiness Scale (ESS) 
The ESS is a self-administered questionnaire with 8 questions (Johns 1991; Appendix 12). The 
patient rates from 0 to 3 their usual chances of dosing off or falling asleep while engaged in 
8 different activities. The total score can range from 0 to 24, with higher rating indicating higher 
average sleep propensity in daily life. The ESS questionnaire will be administered as shown in 
Table 2. 
12.1.8. 
eDiary  
The daily eDiary is an important aspect of this study, and all patients must receive training 
explaining what is being asked of them, when to complete the diary, and how to use the diary 
system effectively. Patients will be trained on use of the diary system at Visit 1. Additionally, 
patients should complete the training on accurate pain reporting and placebo response reduction 
training as required.  
During the 7-day run-in Phase (7 days immediately preceding Visit 2 [Baseline/Randomization 
Visit; Day 1]) patients will be asked to record their worst daily Long COVID pain intensity on 
the 11-point (0−10) NRS scale using 24-hour recall and to assess sleep quality from the previous 
evening, also using an 11-point NRS scale. The average of the 7 days immediately preceding 
Visit 2 (Baseline Randomization Visit; Day 1) will serve as the Baseline pre-treatment scores.  


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During the treatment phase, each evening, the system will prompt the patient to reflect on the 
past 24 hours and record their worst pain intensity, assess their sleep quality from the previous 
evening, and log study drug dosing from the previous night (post--randomization). 
Patients will receive instructions and a password that uniquely identifies them when they log into 
the diary system, along with instructions about what to do if they have difficulty completing the 
diary. 
The diary should be started the evening of Visit 1 and completed daily until Visit 6 (Week 14). 
Patients should be instructed to complete the diary in the evening before dosing. Once the patient 
has properly identified themselves, the diary will prompt answers to the following: 
• Rate your worst Long COVID pain intensity during the last 24 hours on a scale from 
0-10, where 0 is “no pain” and 10 is “pain as bad as you can imagine”. Rate your 
sleep quality last night on a scale from 0−10 where 0 is the “best possible sleep” and 
10 is the “worst possible sleep”. 
After randomization to study drug at Visit 2, the following questions will be added to the daily 
diary (starting in the evening of the day after randomization, Day 2): 
• Did you take your study drug last night? (Yes/No) 
• If yes, how many tablets of study drug did you take last night? (1 tablet/2 tablets) 
 
Appendix 13 details additional information about the eDiary. 
The study staff will be expected to monitor patient compliance throughout the study and will be 
instructed to call the patient should any problems or significant non-compliance be observed. 
During the Screening period, there are diary compliance requirements that must be met in order 
for the patient to qualify for randomization. Patients will receive a reminder to complete their 
diary if they miss diary entries. Patients who miss 2 diary entries will be flagged by the IRT 
system, and site staff will be alerted to contact patients for re-training and to instruct the patient 
on the importance of routine completion of their diary. 
12.2. 
Safety Assessments 
Safety will be assessed by evaluation of AEs, vital signs, responses on the C-SSRS, and by 
clinical laboratory and physical examination findings, including visual inspection of the oral 
cavity. 
12.2.1. 
Adverse Events 
Patients will be monitored for AEs throughout the study. Any clinically significant abnormal 
findings at Screening should be recorded in medical history. AEs will be recorded after the 
informed consent is signed. AEs that are spontaneously reported or 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. Additional 
questions will be triggered for AEs involving the oral cavity (Section 12.2.5).  


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To elicit AEs, non-leading, simple questions with minimal connotations should be used as the 
initial questions at all evaluation points during the study. Examples of these questions can be: 
• How have you felt since your last visit? 
• Have you had any health problems since your last visit? 
If an AE occurs, the Investigator will institute support and/or treatment as deemed appropriate. If 
an AE is unresolved on the last day of the study, an effort should be made to follow up until the 
AE is resolved or stabilized, the patient is lost to follow-up, or there is some other resolution of 
the event. 
There are many symptoms associated with Long COVID that can vary in intensity and frequency 
over time. Only symptoms that worsen or become more frequent and, in the opinion of the 
patient, are outside of their normal experience should be reported as AEs. 
Additional information regarding definition and reporting requirements for AEs, serious adverse 
events (SAEs), and pregnancies is provided in Section 14. 
12.2.2. 
Oral Adverse Events 
Patients should contact the investigative site as soon as possible if they experience a lesion under 
the tongue or any other AE thought to be due to study drug exposure (other than transient 
numbness, tingling or bitter/metallic/unpleasant taste after dosing), specifically to determine 
whether an Unscheduled Visit is necessary prior to the next scheduled visit. If the patient does 
not call the site to discuss the oral cavity AE, the oral cavity exam should be performed at the 
next regularly scheduled visit and any findings noted. If a telephone visit, the patient should be 
queried if there have been any changes or problems in the oral cavity. Patients reporting any 
concerning lesion description or painful processes in the oral cavity possibly related to study 
drug exposure should be strongly urged to come into the clinic for an Unscheduled Visit for an 
oral cavity exam. This exam must be performed by a qualified licensed medical professional who 
has been specifically trained and certified by the Sponsor to conduct this exam. In circumstances 
in which, due to the COVID-19 pandemic it is not possible for the patient to return to the clinic 
for the Unscheduled Visit exam, a clinician certified by the Sponsor to conduct oral cavity 
examination should contact the patient by phone and obtain greater history and description of the 
oral cavity AE by patient, potentially augmented with images of oral cavity taken by the patient 
and sent to the site for the examining clinician to textually document in the oral exam source 
document. 
12.2.3. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire developed by researchers at Columbia University to assess and 
track suicide risk and behavior. This scale is intended to be used by individuals who have 
received training in its administration. The questions contained in the C-SSRS are suggested 
probes. Ultimately, the determination of the presence of suicidal ideation or behavior depends on 
the judgment of the individual administering the scale. 
Two versions of this questionnaire will be utilized in this study. At Visit 1, the 
“Baseline/Screening” questionnaire will be administered, and the recall periods will be “lifetime” 
and “within the past 6 months” for suicidal ideation and “within the past 1 year” for suicidal 


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behavior. Patients whose responses are indicative of suicidal ideation with intent and/or plan (eg, 
Type 3, 4, or 5 suicidal ideation) within the past 6 months or a history of suicidal behavior within 
the past year will be excluded from participation, with recommended referral for appropriate 
intervention. 
At all subsequent visits (Visits 2, 3, 4, 5, and 6), the “Since Last Visit” version of the 
questionnaire will be administered, and the recall period on this will be “since the last visit”.  
12.2.4. 
Physical Examination and Vital Signs 
A complete physical examination will be performed at Visit 1. The complete physical 
examination may exclude rectal, genitourinary, and breast examinations. 
Vital signs (sitting blood pressure and heart rate, temperature, and weight) will be assessed at 
Visits 1, 2, 3, 4, 5, and 6/ET (unless a telephone visit, in which case vital signs will not be 
assessed at Visits 3, 4, 5, and 6/ET). Height will be measured without shoes at Visit 1 only. The 
BMI will be a derived variable, based on height and weight entries (but a Week 14/ET weight 
will not be assessed, if approved by the Medical Monitor for a telephone visit). 
12.2.5. 
Visual Examination of the Oral Cavity 
A thorough examination (visual plus palpation) of the oral cavity will be completed at Visit 1, 
with visual examinations performed at each subsequent study visit (Visits 2, 3, 4, 5 and 6/ET). 
Visual exam of the oral cavity will not be performed if it is a telephone visit. This examination 
should include a careful visual examination of the sublingual area, tongue, buccal mucosa, lips, 
palate, and gums, aided with a tongue depressor, as well as palpation of the lips, hard palate, and 
floor of the mouth.   
Each examination must be performed by a qualified medical professional who has been 
specifically trained and certified by the Sponsor for this examination. An oral cavity examination 
may also be required at an Unscheduled Visit if a patient reports an oral AE that requires follow-
up prior to the next scheduled visit. 
12.2.6. 
Clinical Laboratory Assessments 
The clinical laboratory evaluations to be performed in this trial are listed in Table 3. Those 
marked as screening tests will be performed at Screening only. All other tests will be performed 
at the Screening Visit, Visit 4/Week 6, and at Visit 6/ET (Week 14), aside from urine pregnancy 
tests and ad hoc urine drug screens. Testing for HIV, HCV, and hepatitis B surface antigen 
(HBsAg) will be performed at Screening and may be performed at other visits at Investigator’s 
or Sponsor’s discretion.  
With the exception of the urine pregnancy test or an ad hoc urine drug screen, 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 the clinical laboratory manual. 
As per Exclusion Criterion #14 any patient with evidence during the preceding year of drug or 
alcohol use disorder by MINI or history is ineligible.  


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A centrally analyzed UDS will be performed at Visit 1. If the patient has a positive drug screen 
at Visit 1 due to a drug of abuse (eg, cocaine, methamphetamine, ecstasy) or due to a non-
disclosed opioid, amphetamine, or benzodiazepine, then he/she should be screen-failed. As 
discussed in Section 9.2, patients utilizing cannabis/THC are to be excluded if MINI criteria are 
met for greater than MILD Cannabis Use Disorder during the preceding 12 months, OR if the 
Investigator is concerned that the patient’s use of cannabis/THC could interfere with patient’s 
ability to provide reliable data or comply with the protocol. Otherwise, patients utilizing 
cannabis or THC products are allowed, with caution.  
The screening drug screen will test for THC to provide the Investigator with information 
regarding exposure, and to ensure that all usage is disclosed and taken into consideration when 
conducting MINI Module J. Repeat testing of THC is not necessary for patients testing positive 
for cannabis/THC at screening. 
Any patient deemed appropriate for washout of a prescription opioid, benzodiazepine, or 
amphetamine will require a repeat UDS before the beginning of their 7 days of baseline data 
collection leading up to Visit 2, the results of which must be negative and available for review 
before randomization may occur. Therefore, these patients will need to return for an 
Unscheduled Visit after the first 2 weeks of Washout have been completed. All benzodiazepine 
drug screening must be sent to the central laboratory for analysis; hence, results may be delayed. 
All other repeat urine drug screening may be conducted on site. Patients do not have to wait for 
confirmation of negative centralized benzodiazepine results before starting their 7-day baseline 
data collection phase, but all results must be confirmed negative prior to randomization.  
Patients with a positive screening UDS due to an allowed prescription drug (eg, headache 
remedies containing butalbital) do not require further drug screening.  
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. Clinically significant 
abnormalities in laboratory values after the Screening Visit labs will be recorded as AEs. 
NOTE: A screening TSH level greater than 1.5 times higher than the upper limit of normal, 
glycated hemoglobin (HbA1c) > 7.5%, or ALT or AST level > 2 times the upper limit of normal, 
is exclusionary; however, the patient may remain in screening to undergo repeat liver function 
assessments if a transient abnormality (eg, viral illness; effects of a medication being 
discontinued, etc.) is thought to be responsible for their initial elevation.  


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Table 3: 
Clinical Laboratory Assessments 
Clinical chemistry 
Hematology 
Alanine aminotransferase (ALT/SGPT) a 
Hematocrit 
Alkaline phosphatase 
Hemoglobin 
Aspartate aminotransferase (AST/SGOT) a 
Erythrocyte sedimentation rate (ESR) c 
Bicarbonate 
MCH concentration (MCHC) 
Bilirubin (direct and total) 
Mean corpuscular hemoglobin (MCH) 
Blood urea nitrogen (BUN) 
Mean corpuscular volume (MCV) 
Calcium 
Platelet count 
Chloride 
Red blood cell (RBC) count 
Cholesterol (total) 
WBC differential 
Creatine kinase (CK) 
Neutrophil count (absolute and %) 
Creatinine 
Lymphocyte count (absolute and %) 
Glucose 
Monocyte count (absolute and %) 
Lactate dehydrogenase (LDH) 
Eosinophil count (absolute and %) 
Phosphorus 
Basophil count (absolute and %) 
Potassium 
White blood cell (WBC) count 
Protein (albumin and total) 
Red blood cell distribution width (RDW) 
Sodium 
Viral testing  
HbA1c b,c  
Anti-HIV antibodies c 
Thyroid-stimulating hormone (TSH) c,d 
Anti-HCV antibodies c 
Free T4 only if TSH is outside of normal limits 
HBsAg c  
Pharmacogenomic testing (optional; can be obtained at any 
visit post-Screening, including an Early Termination Visit. 
However, it is preferred that these samples are collected at 
Visit 2) 
Other 
Urinalysis 
Serum Pregnancy Test c,e 
Urine Pregnancy Test (qualitative dipstick) e 
Urine Drug Screen f 
a Level greater than 2 times the upper limit of normal is an exclusion (if persistent upon repeat). 
b HbA1c ≥ 7% is exclusionary at Visit 1. 
c Test performed at Visit 1 only. 
d TSH level greater than 1.5 times higher than the upper limit of normal is exclusionary at Visit 1. 
e  Pregnancy testing for females of child-bearing potential only. A positive pregnancy test is exclusionary (Visit 1 or Visit 2) or 
mandates withdrawal from the study (all other visits). 
f  Urine drug screening will be conducted on all patients at Screening and, if necessary, prior to the beginning of the 7-day 
baseline data collection phase in patients washing off opioids, amphetamines, or benzodiazepines and who otherwise qualify 
for the study. 
12.2.7. 
Electrocardiogram 
A 12-lead ECG will be performed at Visit 1 and reviewed by the Investigator for the purpose of 
excluding from participation patients who have either a history of or current evidence of 
clinically significant cardiac disease (eg, significant arrhythmias or heart block, left bundle 
branch block, heart failure, symptomatic coronary artery disease, myocardial infarction within 
the preceding 2 years), or a QTcF at Screening > 450 msec if male or 470 msec if female. The 
ECG interpretation by the Investigator will be recorded in the CRF as normal, abnormal but 
clinically insignificant, or abnormal and clinically significant. In addition, the standard ECG 
parameters including rhythm, heart rate, and intervals for RR, QT, PR, QRS, and QTcF 
(Fridericia’s correction) will be recorded. 
If the Investigator has any concerns about the eligibility of a patient or wishes to confirm his/her 
assessment, the Investigator should consult with the Medical Monitor for this study. 


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12.3. 
Pharmacogenomic Testing (Optional) 
For optional pharmacogenomic analyses, blood samples will be obtained from each patient who 
provided separate written, signed informed consent for pharmacogenomic analysis. These 
samples may be obtained at any post-screening visit, including an ET Visit; however, it is 
preferred that they are collected at Visit 2 whenever possible. The purpose of this testing is to 
allow for whole genome sequencing (WGS) and analysis for allelic polymorphisms related to 
treatment response to TNX-102 SL.  
Please refer to the Laboratory Manual for additional details on the sample collection methods 
and materials used in this study. 
Unused extracted DNA may be stored up to 15 years and potentially utilized to develop a 
pharmacogenomic test for determining the likelihood of treatment response to TNX-102 SL. A 
decision not to participate in optional pharmacogenomic testing will not affect the patient’s 
eligibility for the main study. Patients have the right to stop participating at any time during the 
study or during the time of sample storage, and, if a patient decides to withdraw from the 
pharmacogenomics portion of this study, any remaining sample will be destroyed and not used 
for further research. Data collected before a patient’s withdrawal from the pharmacogenomics 
portion of this study will remain in the research database and included in the Sponsor’s analyses 
and reports. 
 


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13. 
STATISTICAL CONSIDERATIONS AND ANALYSES 
A complete description of the statistical analyses to be performed will be provided in the 
study -specific statistical analysis plan (SAP), which will be finalized prior to database lock and 
the unblinding of study treatments. 
Baseline will be defined as those values recorded closest to, but prior to administration of, the 
first dose of study drug. 
13.1. 
Populations for Analysis 
 In the case that the study goes to full enrollment or has a sample size increase, the following 
analysis populations are planned for this study: 
• All Patients: used for summaries of dispositions of patients; tabulations of dispositions 
may also use the populations below. 
• Safety population: all patients who receive at least one dose of the investigational 
product. All safety analyses will be performed using this population, analyzed as treated. 
• Intention-to-treat (ITT) population: all patients who are randomized. This is the primary 
population for efficacy analyses, and patients will be analyzed based on their randomized 
treatment. 
In the case of an early stop for efficacy or for futility from the interim analysis, the following 
populations will be utilized: 
• All Patients: used for summaries of dispositions of patients; tabulations of dispositions 
may also use the populations below. 
• Interim Safety population: all patients who receive at least one dose of the investigational 
product and included in the cohort of interim analysis patients. All safety analyses will be 
performed using this population, analyzed as treated. 
• Interim ITT population: all patients who are randomized and included in the cohort of 
interim analysis patients. This is the primary population for efficacy analyses, and 
patients will be analyzed based on their randomized treatment. 
• Full Safety population: all patients who receive at least one dose of the investigational 
product. This will be used for supportive safety analyses on all patients exposed in the 
study, analyzed as treated. 
13.2. 
Estimate of Sample Size 
The study is planned to enroll approximately 470 patients total in a 1:1 randomization, 
235 patients in each of the TNX-102 SL 5.6 mg and placebo arms. Using a two-sided test with an 
alpha level of 0.05, a sample size of 235 per group provides a power of at least 90% if the effect 
size is 0.3. 


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13.3. 
Assessment of Demographic and Baseline Characteristics 
Demographic and baseline characteristics such as age, gender, race/ethnicity, height, weight, 
BMI, family status, education, employment status, smoking history, and MINI modules (A, C, I, 
J, K, O) will be summarized by treatment group (TNX-102 SL and placebo) and overall using 
descriptive statistics. 
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 by treatment group. 
13.4. 
Efficacy Analyses 
13.4.1. 
Primary Efficacy Analysis 
The primary efficacy parameter will be the contrast between TNX-102 SL and placebo in the 
weekly mean change in worst pain score from Baseline to Week 14. The weekly pain score will 
be based on the weekly average of the daily diary patient self-reported 24-hour recall worst Long 
COVID pain intensity scores using an 11-point (0−10) NRS. A weekly value will be calculated 
as long as at least one daily measure is recorded. 
The primary ITT analysis will provide the following causal estimand for the primary analysis: 
the difference in the weekly mean change from Baseline of the daily patient self-reported 24-
hour recall worst Long COVID pain intensity rating using an 11-point (0−10) NRS evaluated at 
the Week 14 endpoint in all randomized patients attributable to the initially randomized 
treatment assignment.  
The primary analysis will use a Mixed Model Repeated Measures (MMRM) approach with 
multiple imputation (MI) for missing data. Covariates in the model will include the fixed 
categorical effects of treatment, pooled site (with small sites pooled into a single large site), 
study week, and treatment by study week interaction, as well as the continuous fixed covariates 
of baseline score and baseline score by study week interaction. An unstructured covariance 
structure will be used to model the within-patient errors. If this analysis fails to converge, the 
following structures will be tested in this order: first order ante dependence, heterogeneous first 
order autoregressive, heterogeneous compound symmetry, and compound symmetry with the 
first to give convergence used. The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom (DDFM) with the unstructured matrix; other covariance 
structures will utilize the sandwich matrix and the Statistical Analysis System (SAS) default 
DDFM. The least square (LS) means and differences across the 20 MI repeats will be combined 
using SAS procedure MIANALYZE (Rubin, 1976).  Significance testing will be based on least-
squares means and two-sided 95% confidence intervals will be presented. The p-values will be 
compared against a two-sided alpha of 0.046. 
13.4.2. 
Missing Data Imputation 
For individual daily pain scores, since a mean is used in the calculation of the primary endpoint, 
it is not necessary to replace values missing on random intermittent days; weeks will have 
average values as long as a single value for that week is present. 


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. 
13.5. 
Sensitivity Analyses 
The primary analysis will be followed by several sensitivity analyses. The SAP will include full 
details of the sensitivity analyses planned for this study. 
13.6. 
Secondary Efficacy Analyses 
Secondary efficacy analyses will be based on the ITT population. For the purposes of possible 
label claims and reported p-values entered into the multiplicity algorithm, an approach identical 
to the primary analysis will be used for all key secondary continuous outcomes.  
Analyses of other continuous secondary endpoints will be similar to the analysis of the primary 
endpoint, utilizing MMRM, but without MI for missing data. Significance tests of treatment 


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differences will be based on least-squares means, and corresponding 95% confidence intervals 
will be calculated. 
A categorical analysis of PGIC will compare the treatment arms with a difference in proportions 
Z test (equivalent to a Pearson’s Chi Squared).  Subjects with results of “very much improved” 
or “much improved” (defined as responders) will be compared to all other categories (defined as 
non-responders).  Subjects with missing data will be considered non-responders.  The 
percentages of responders and the 95% CIs of the percentages as well as the difference in the 
percentages and its 95% CI will be reported. A summary of frequency counts for all PGIC 
responses for each time point will be presented; Week 14 is of primary interest and all other time 
points are considered exploratory.  
To adjust for multiplicity and to control for overall type I error, a sequential test procedure will 
be applied to the primary and key secondary efficacy endpoints. If the primary analysis produces 
a result that is statistically significant at the two-sided 0.046 level, a significance level of 0.046 
will be used for comparing the key secondary endpoints in an ordered fashion. If the analysis for 
a key secondary endpoint does not produce a statistically significant result at the 0.046 level, 
then the remaining key secondary endpoint analyses will automatically be considered non-
significant regardless of the p-value produced. In the case of an early stop for efficacy, this will 
be the same as the stopping criteria for the primary efficacy endpoint (secondary endpoints will 
be tested at p-value = 0.005, one-sided).  
The order in which the key 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 
inference. Full details regarding the statistical analyses for the listed endpoints, including 
graphical presentations, can be found in the SAP. 
13.6.1. 
Exploratory Efficacy Analyses 
Exploratory efficacy analyses will be based on the ITT population. Details on exploratory 
efficacy analyses can be found in the SAP. 
13.7. 
Safety Analyses 
Safety analyses will be performed using the Safety Population. The analysis of safety 
assessments in this study will include summaries of the following safety and tolerability data 
collected for each patient: 
• Incidence of AEs 
• Changes from Baseline in clinical laboratory tests 
• Changes from Baseline in vital signs 
• Changes from Baseline in physical examination findings including examination of the 
oral cavity 
• Monitoring suicidality using the C-SSRS 


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All AEs, treatment-emergent adverse events (TEAEs), and SAEs will be coded using the 
MedDRA. 
An AE summary table will be presented for the following: 
• All TEAEs 
• TEAEs by severity 
• TEAEs leading to study drug discontinuation  
• TEAEs by relationship 
• SAEs 
• Oral cavity TEAEs 
• Oral cavity TEAEs by severity 
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, oral 
cavity 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. 
In the AE data listings, all AEs will be displayed. 
Laboratory data include analytes for chemistry and hematology, and these will be summarized by 
treatment and visit for the Safety Population. Descriptive summaries of actual values and 
changes from Baseline will be presented by study visit and last available assessment for each 
clinical laboratory analyte and 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. For each laboratory analyte, 
shifts in assessments of abnormality from Baseline to each scheduled time point will be 
presented in shift tables. 
A by-patient listing of all clinical laboratory data will also be provided. 
Descriptive summaries (n, mean, standard deviation, median, range, minimum, and maximum) 
of actual values and changes from Baseline at each assessment time point and last-available 
assessment will be calculated for vital signs including weight, BMI, body temperature, pulse 
rate, systolic blood pressure, and diastolic blood pressure. Ninety-five- percent confidence 
intervals will be presented for change from Baseline. 
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 Visits will be summarized by visit and treatment group.  
Additionally, the number of subjects with increase over baseline in suicidal ideation at any time 


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point will be reported.   The maximum ideation across all visits for a subject will also be 
summarized with counts and percentages both for all subjects and among subjects with an 
increase in ideation.  Likewise, the count and percentage of subjects with any suicidal behavior 
will be reported along with a summary of the most extreme behavior each subject reported. 
Physical examination data and oral examination data will be presented in data listings. 
13.8. 
Interim Analyses 
An interim analysis will be performed when approximately 50% of the initially planned 
enrollment is evaluable for efficacy assessments.  This interim analysis will be performed by an 
unblinded team separate from the team responsible for the conduct and analysis of the study. An 
Independent Data Monitoring Committee (IDMC) will review the data and recommend to the 
Sponsor one of the following: 
• 
Stop the study early for efficacy if the one-sided alpha for the primary endpoint is less 
than 0.005 
• 
Increase the sample size by a fixed amount 
• 
Keep the current sample size and continue as planned 
• Stop the study early for futility if conditional power at interim is <20%  
The recommendations are nonbinding, and the Sponsor may make adjustments other than those 
detailed above; however, the Sponsor will receive no information other than the 
recommendations listed.  
These assessments will be based on the primary analysis of the primary outcome; however, the 
committee will have additional outputs such as demographics, dispositions, and other key 
efficacy analyses. If the p-value for the primary falls short of stopping for efficacy, but the 
conditional power (CP) based on this is still greater than 90%, then the IDMC will recommend 
no change in sample size.  If the conditional power is less than 90% but greater than or equal to 
20% the IDMC will recommend an increase in sample size, with the maximum increase limited 
to 220 additional subjects and any increase done in blocks of 20 subjects. The increase will be 
chosen with the goal of increasing the sample size by the minimum number of subjects sufficient 
to raise the conditional power to at least 90%.  If the 220 subject increase is insufficient to 
increase the power over 90%, an increase of 220 patients will be recommended as long as the CP 
at the original planned sample size of 470 patients is over 20%. If the CP is below 20%, then the 
recommendation will be to halt the study for futility.  No further information will be provided to 
the sponsor beyond this recommendation. 
The interim analysis will be conducted approximately 18 weeks after randomization of 
approximately 235 participants, i.e. when approximately 50% of the initially planned participant 
enrollment (470) is evaluable for efficacy assessments (approximately 14 weeks); and related 
data cleaning, database freeze, and administrative tasks have been completed on this cohort 
(approximately 4 weeks).  
In the case of an early stop for efficacy or futility, all ongoing subjects will be asked to return to 
the clinic and complete an early termination visit, and the study will be halted once all subjects 
have completed their termination visit.   


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13.8.1. 
P-value Adjustment for the Interim Analysis 
 The interim analysis will test the primary and key secondary outcomes at the one-sided 
alpha=0.005 for the purposes of an early stop for efficacy; if the study is not stopped, the 
corresponding final alpha level to account for the first stage alpha spend (should the study 
continue to full enrollment) will be 0.046 (two-sided).  For simplicity, 95% confidence intervals 
will be reported throughout, but for the purposes of study success, label claims and multiplicity, 
p-values will be compared to 0.046. 
Data from the interim and post-interim cohorts will be combined using the inverse normal 
method (Cui et al. 1999): 
𝑍1 = Φ−1(1 −𝑝1) 
and 𝑍2 = 𝑤1𝑍1 + 𝑤2Φ−1(1 −𝑝2)           (1) 
where: 
Z1 = the Z statistic for the first stage 
Z2 = the combination test statistic at the end of the second stage 
wi = the weighting applied for each associated Z statistic 
p1 = the first stage p-valuep2 = the second stage p-value based on the second stage participants 
The weights are defined prospectively according to the square-root of the planned proportion of 
participants in the two stages, relative to the preplanned total enrollment of 470 participants, as 
w𝑖 = √0.5. To control the type I error, adaptive changes of the stage wise sample sizes will not 
lead to changes of the weights (Lehmacher and Wassmer. 1999). 
  
Full details of the interim analysis will be included in the SAP and/or IDMC Charter which will 
be finalized prior to execution of the interim analysis. 


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14. 
DEFINITIONS, RECORDING, AND REPORTING OF ADVERSE 
EVENTS 
14.1. 
Definition of Adverse Events 
According to International Council for Harmonisation (ICH) guidance E2A, Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, an AE is any untoward 
medical occurrence in a patient or clinical investigation patient administered a pharmaceutical 
product and which is not necessarily required to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
A TEAE is an AE that either commenced following initiation of study treatment or was present 
prior to study treatment but increased in frequency or severity following initiation of study 
treatment. 
14.2. 
Adverse Event Recording 
14.2.1. 
Coding the Adverse Event 
Standard medical terminology should be used in describing AEs. MedDRA v24.1 and 
WHODRUG Global (B3 format) will be used as the standard coding dictionary for AEs and in 
describing the patient’s medical history, and the WHO Drug Dictionary will be used to code 
concomitant medications. Informal descriptions should be avoided. 
14.2.2. 
Severity of Adverse Event 
AEs should be graded as mild, moderate, or severe using the following definitions. 
• Mild: Awareness of signs or symptoms, but easily tolerated and of minor irritant type 
causing no loss of time from normal activities. Symptoms do not require therapy or a 
medical evaluation; signs and symptoms are transient. 
• Moderate: Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 
• Severe: Events interrupt the participant’s normal daily activities and generally require 
systemic drug therapy or other treatment; they are usually incapacitating. 
To make sure there is no confusion or misunderstanding of the difference between the terms 
“serious” and “severe,” which are not synonymous, the following note of clarification is 
provided. The term “severe” is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe myocardial infarction); the event itself, however, maybe of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious,” which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient's life or functioning. Seriousness (not severity) serves as a 
guide for defining regulatory reporting obligations. 


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14.2.3. 
Relationship of Adverse Events to Study Drug 
The Investigator will assess the potential relationship of the AE to study drug using the following 
descriptions. 
• Not Related: This category applies to an AE that is clearly not related to the study 
drug 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. 
14.3. 
Serious Adverse Events (SAEs) and Serious Adverse Drug Reactions 
Any SAE that occurs at any time during the study, including a clinically significantly abnormal 
laboratory test result that is considered serious, must be reported to Tonix or its designee(s) so 
that Tonix may comply with regulatory obligations. If the SAE is life-threatening or fatal, it must 
be reported to Tonix or its designee(s) immediately, by facsimile and telephone. For these and all 
other SAEs, an SAE report form must be completed and sent by facsimile or email to Tonix or 
its designee(s) within 1 working day of the site’s initial awareness of the event. These 
requirements apply equally to all patients, regardless of the study phase or the at-risk patient’s 
treatment assignment or dosage. 
An SAE (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 


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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. The 
development of C-SSRS suicidal ideation type 4 (intent) or type 5 (specific plan and intent) any 
time after consenting to the study should always be reported as an SAE. Additionally, since only 
Types 1 and 2 are allowed at Screening or Baseline, the development of C-SSRS Type 3 (method 
but no plan or intent) after consenting should always be reported as an AE.  
Any death occurring during the study, during the per-protocol follow-up period, or reported to 
the Investigator after study participation (no required post-study time limit) must be reported to 
Tonix or its designee(s) immediately, whether or not it is considered treatment-related. Initial 
SAE reports must be followed by detailed descriptions. These should include copies of hospital 
case records and other documents when requested. Telephone reports must be confirmed 
promptly either by facsimile or by e-mail. For reporting SAEs, Tonix’s designated Medical 
Monitor should be called, and the relevant forms submitted to Premier pharmacovigilance within 
24 hours of the site’s awareness of the SAE. The contact information for the Medical Monitors is 
as follows: 
The Investigator, or the Sponsor or designee in the case of a central institutional review board 
(IRB), also must notify the ethics committee (EC)/IRB of the occurrence of the SAE, in writing, 
as soon as is practicable and in accordance with local law. A copy of this notification must be 
provided to Tonix or its designee. 
In the event of an SAE that meets the criteria for expedited reporting, an investigational new 
drug (IND) Safety Report will be prepared for submission to the FDA. 
Clinical investigators also have the authority to unblind their own SAE patients if/when the 
unblinded treatment information could impact the patient’s clinical management. There is a 
module within the IRT system for investigators’ use if “emergency” unblinding is required; 
however, the Investigator is requested to confer with the Medical Monitor before taking any 
action. The need for emergency unblinding is not expected for this study, in light of the nature of 
the study drug.  


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14.4. 
Pregnancy 
The active pharmaceutical product in TNX-102 SL is cyclobenzaprine HCl, which is in 
Pregnancy Category B (AMRIX® Package Insert, 2020). All pregnancies occurring during the 
study (after exposure to study drug) or within 28 days after discontinuation of study drug must be 
followed until resolution (ie, birth or voluntary or spontaneous termination of the pregnancy). All 
women of childbearing potential are therefore required to continue contraception for 28 days 
after study drug discontinuation. Any patient found to be pregnant at any time during the study 
will be withdrawn from the study immediately. Any pregnancy outcome that meets the criteria 
for an SAE will be reported as an SAE. 


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15. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY 
15.1. 
Protocol Modifications and Deviations 
The Investigator will make all reasonable efforts to comply with the written protocol and 
protocol amendments. All protocol modifications must be reviewed and approved by the 
appropriate EC/IRB before the revised protocol can be implemented. Emergency revisions that 
eliminate an apparent hazard to patients do not require preapproval by the EC/IRB. However, the 
EC/IRB must be notified, in writing, as soon as possible after the modification has been made. A 
copy of this communication must be forwarded to Tonix. 
15.2. 
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 enroll 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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16. 
ETHICAL CONSIDERATIONS 
16.1. 
Ethical Conduct of the Study 
This protocol is written in accordance with the principles established by the 18th World Medical 
Assembly General Assembly (Helsinki, 1964) and amendments and clarifications adopted by 
subsequent General Assemblies. The Investigator will make sure that the study described in this 
protocol is conducted in full conformance with those principles, the protocol, current FDA 
regulations, ICH Good Clinical Practices (GCP) guidelines, Good Laboratory Practices (GLP) 
guidelines, local ethical and regulatory requirements, including the Federal Food, Drug and 
Cosmetic Act, US applicable Code of Federal Regulations (title 21), and any EC/IRB 
requirements relative to clinical studies. As required by the US FDA, the study drug may not be 
shipped to any participating Investigator until the requisite study documentation has been 
submitted to the IND. 
Should a conflict arise, the Investigator will follow whichever law or guideline affords the 
greater protection to the individual patient. The Investigator will also make sure he or she is 
thoroughly familiar with the appropriate administration and potential risks of administration of 
the study drug, as described in this protocol and the Investigator’s Brochure, prior to the 
initiation of the study. 
16.2. 
Ethics Committee/Institutional Review Board (EC/IRB) Review 
The EC/IRB must be a properly constituted board or committee operating in accordance with 
21 CFR Part 56, “Institutional Review Boards.” This protocol, any protocol amendments, the 
associated 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. 
16.3. 
Written Informed Consent 
It is the responsibility of the Investigator to obtain signed written informed consent from each 
potential study patient prior to the conduct of any screening or other study procedures. This 
written informed consent will be obtained after the methods, objectives, and potential risks of the 
study have been fully explained to the potential patient. The Investigator must explain to each 
patient that he or she is completely free to refuse to enter the study or to withdraw from it at any 
time. NOTE: Patients on antidepressant therapy should be warned of a potential serious drug 
interaction and should be advised to contact their study site immediately if they experience any 
symptoms that might represent possible serotonin syndrome, including fever, confusion or 
agitation, hallucinations, sweating, high or low blood pressure, rapid heart rate, tremor, muscle 
rigidity, or nausea, vomiting, or diarrhea. 


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The patient should also be asked in the ICF for permission for the Principal Investigator or his 
designee to contact the patient’s other personal physicians, as appropriate, concerning 
participation in the study. 
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/IRB, prior to 
subsequently obtaining each patient’s consent. 
Receipt of written informed consent will be documented in each patient’s or potential patient’s 
CRF. The signed ICF must remain in each patient’s study file and must be available for 
verification by study monitors at all times. 
Separate written, signed informed consent must be obtained if the patient is to participate in the 
optional pharmacogenomic assessment. 
 


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17. 
DATA HANDLING, RECORD KEEPING, MONITORING AND 
AUDITS 
17.1. 
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 and 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 patient 
information will not be made publicly available unless mandated by applicable laws and 
regulations. 
17.2. 
Maintaining Essential Clinical Documents 
Study site files for the retention of regulatory documents will be established at the beginning of 
the study, maintained for the duration of the study, and retained according to FDA and ICH/GCP 
guidelines and applicable regulatory requirements. The records maintained must be adequate to 
fully document appropriate protection of study patients/patients, the validity of the study, the 
integrity of the data, and the manner in which the study was conducted. 
The Investigator’s site file, copies of protocols, CRFs, originals of test result reports, drug 
disposition logs, correspondence, records of written informed consent, and other documents 
pertaining to the conduct of the study must be kept on file by the Investigator and in readily 
accessible order for at least 2 years after the last approval of a marketing application, until at 
least 2 years have elapsed after formal discontinuation of the clinical development of the 
investigational product, or according to local regulatory requirements. No study document may 
be destroyed without prior written consent from Tonix or its designee. Should the Investigator 
wish to withdraw from the responsibility of keeping the study records, custody must be 
transferred to a person willing to accept the responsibility. Tonix must be notified in writing in 
advance if a custodial change is to occur. It is important that the Investigator remain ready to 
provide background information from the archived study records on request. 
The Sponsor or designee will maintain adequate study records for at least 2 years after the last 
approval of a marketing application or for at least 2 years after clinical development of the study 
drug for the indication being studied has been discontinued. After that period, the sponsor will be 
contacted to determine whether the study records will be forwarded to the sponsor, destroyed, or 
kept at the location of the designee or another facility for a longer period of time. 
17.3. 
Data Handling 
Unless otherwise specified, procedures, data collection and evaluation will be conducted as per 
the Standard Operating Procedures of the contract research organization (CRO). The Investigator 
will assume the responsibility of ensuring the completeness and accuracy of the clinical data. All 
data will be verified for quality control and will also be patient to audits from Tonix or designee 
to ensure quality. 


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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 that 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. 
17.4. 
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 are collected via paper (patient questionnaires, etc.), the data must be entered into 
the CRF and verified that it has been transcribed correctly. 
17.5. 
Clinical Laboratory Certification 
A central clinical laboratory will be used to analyze all samples in this study, with the exception 
of the post-Screening urine pregnancy tests 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. 
17.6. 
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. In extenuating circumstances related to the COVID-19 
pandemic, remote monitoring will be permissible. 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 


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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. 
17.7. 
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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18. 
CONFIDENTIALITY 
18.1. 
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, patients should not be identified by their names, but 
rather by their initials and the assigned study identification numbers. The Investigator should 
keep a separate record of the patient initials, randomization codes, patient names, address, and 
contact information. Documents that contain the names associated with these initials and codes 
are not for submission to Tonix or its agents (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. 
18.2. 
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 toward 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. 
18.3. 
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.  
 
 
 


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19. 
REFERENCES 
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Sequelae of SARS-CoV-2 Infection (PASC): Defining the Post COVID Syndrome. J Prim Care 
Community Health. 2021;12:1-8. 
Brummett CM, Goesling J, Tsodikov A, Meraj TS, Wasserman RA, Clauw DJ, Hassett AL. 
Prevalence of the fibromyalgia phenotype in patients with spine pain presenting to a tertiary care 
pain clinic and the potential treatment implications. Arthritis Rheum. 2013;65(12):3285-92.  
Brummett CM, Janda AM, Schueller CM, Tsodikov A, Morris M, Williams DA, Clauw DJ. 
Survey Criteria for Fibromyalgia Independently Predict Increased Postoperative Opioid 
Consumption after Lower-extremity Joint Arthroplasty: A Prospective, Observational Cohort 
Study. Anesthesiology. 2013;119(6):1434-43.  
Brummett CM, Urquhart AG, Hassett AL, Tsodikov A, Hallstrom BR, Wood NI, Williams DA, 
Clauw DJ. Characteristics of fibromyalgia independently predict poorer long-term analgesic 
outcomes following total knee and hip arthroplasty. Arthritis Rheumatol. 2015;67(5):1386-94. 
Brummett CM, Lohse AG, Tsodikov A, Moser SE, Meraj TS, Goesling J, Hooten M, Hassett 
AL. Aberrant analgesic response to medial branch blocks in patients with characteristics of 
fibromyalgia. Reg Anesth Pain Med. 2015;40(3):249-54.  
Brummett CM, Bakshi RR, Goesling J, et al. Preliminary validation of the Michigan Body Map. 
Pain. 2016;157(6):1205-12. 
Chopra V, Flanders SA, O’Malley M. Sixty-day outcomes among patients hospitalized with 
COVID-19. Ann Intern Med. 2020;174(4):576-8. 
Clauw DJ, Hauser W, Cohen SP, Fitzcharles MA. Considering the potential for an increase in 
chronic pain after the COVID-19 pandemic. Pain. 2020;161(8):1694-7. 
Crook H, Raza S, Nowell R, et al. Long COVID – Mechanisms, risk factors, and management. 
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outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9:105-21. 
Fitzcharles MA, Cohen SP, Clauw DJ, et al. Nociplastic pain: towards an understanding of 
prevalent pain conditions. Lancet. 2021;397:2098-110. 
Gagnier JJ, Bergmans RS, Clauw DJ. Musculoskeletal Components of Post-Acute Sequelae of 
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from hospital: a cohort study. Lancet. 2021;397(10270):220-32. 
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Functional Status Scale in adult subjects with COVID‑19. Health Qual Life Outcomes. 
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Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep. 2011;34(5):601-8. 
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Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary 
diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res 
(Hoboken). 2010;62(5):600-10. 
Wolfe F, Clauw DJ, Fitzcharles MA, et al. Fibromyalgia criteria and severity scales for clinical 
and epidemiological studies: A modification of the ACR Preliminary Diagnostic Criteria for 
Fibromyalgia. J Rheumatol. 2011;38(6):1113-22. 
World Health Organisation (WHO) Working Group on the Clinical Characterisation and 
Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 
clinical research. Lancet Infect Dis. 2020;20(8):e192-7. 
World Health Organisation (WHO). A clinical case definition of post COVID-19 condition by a 
Delphi consensus. 6 October 2021. Available at: https://www.who.int/publications/i/item/WHO-
2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1 
 
 


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20. 
APPENDICES 
Appendix 1: WHO COVID-19 8-Category Ordinal Scale of Disease Severity 
(Reference: WHO Working Group on the Clinical Characterisation and Management of COVID-
19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet 
Infect Dis. 2020;20(8):e192-7.) 
Value 
Status 
1 
Not hospitalized, no limitation on activities 
2 
Not hospitalized, limitation on activities and/or requiring home 
oxygen 
3 
Hospitalized, not requiring supplemental oxygen - no longer 
requires ongoing medical care 
4 
Hospitalized, not requiring supplemental oxygen - requiring ongoing 
medical care (COVID-19 related or otherwise) 
5 
Hospitalized, requiring supplemental oxygen 
6 
Hospitalized, on non-invasive ventilation or high flow oxygen 
devices 
7 
Hospitalized, on invasive mechanical ventilation or extracorporeal 
membrane oxygenation (ECMO) 
8 
Death 
 
 
 


 
 
 
 
 
 
 
  
Appendix 2: Modified Michigan Body Map (mMBM) (Brummett et al. 2015a) 
 
 
 
 
 


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Appendix 3: In-clinic assessment of average daily Long COVID Pain (7-day recall) 
 
 
 
 
 
 


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Appendix 4: Post-COVID-19 Functional Status Scale (PCFS)  
 
 
 
 
 
 
 


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Appendix 5: List of CYP3A4 Inhibitors 
Taken from Table 3, FDA Draft Guidance for Industry:  Drug Interaction Studies—Study 
Design, Data Analysis, Implications for Dosing, and Labeling Recommendations; Feb 2012; 
updated 26 Sept 2016). Excluded strong CYP3A4 inhibitors are listed in the far-left column of 
the table.  
 
Strong Inhibitors  
 
≥ 5-fold increase in AUC   
Or, > 80% decrease in CL  
Moderate Inhibitors   
 
≥ 2 but < 5-fold increase in AUC   
Or 50-80% decrease in CL  
Weak Inhibitors  
 
≥ 1.25 but < 2-fold increase in  
AUC   
Or, 20-50% decrease in CL  
CYP3A4  
boceprevir  
clarithromycin   
cobicistat  
conivaptan  
danoprevir  
(darunavir)* 
(dasabuvir)* 
diltiazem 
elvitegravir  
grapefruit juice   
idelalisib 
indinavir   
itraconazole  
ketoconazole   
lopinavir    
mibefradil  
nefazodone  
nelfinavir  
(ombitasvir)* 
paritaprevir  
posaconazole  
ritonavir   
saquinavir   
telaprevir  
telithromycin  
tipranavir  
troleandomycin  
voriconazole  
amprenavir  
aprepitant  
atazanavir  
cimetidine  
ciprofloxacin  
clotrimazole  
crizotinib  
cyclosporine    
dronedarone  
erythromycin  
fluconazole  
fluvoxamine  
fosamprenavir  
imatinib  
tofisopam  
verapamil  
alprazolam  
amiodarone  
amlodipine  
atorvastatin  
bicalutamide  
chlorzoxazone  
cilostazol  
fosaprepitant  
fluoxetine  
gingko  
goldenseal   
isoniazid  
istradefylline  
ivacaftor  
lapatinib  
lomitapide  
nilotinib  
oral contraceptives  
pazopanib  
ranitidine  
ranolazine  
tacrolimus  
tipranavir/ritonavir  
ticagrelor  
zileuton  
Source:  Table 3-2, 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm  
* Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution should be used 
when extrapolating the observed effect of ritonavir alone to the effect of combination regimens on CYP3A activities. 
 


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prohibited.  
Appendix 6: Sheehan Disability Scale 
 
 


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prohibited.  
Appendix 7: PROMIS – Sleep Disturbance Scale 
 


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prohibited.  
Appendix 8: PROMIS – Fatigue Scale  
 


Protocol No. TNX-CY-PA201 
 
 
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prohibited.  
Appendix 9: PROMIS – Cognitive Function - Abilities 
 
 
 


Protocol No. TNX-CY-PA201 
 
 
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prohibited.  
Appendix 10: Patient Global Impression of Change (PGI-C) Assessment 
 
 
 
 
 
 


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prohibited.  
Appendix 11: Insomnia Severity Index (ISI) 
 


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prohibited.  
Appendix 12: Epworth Sleepiness Scale (ESS) 


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prohibited.  
Appendix 13: eDiary  
• The eDiary will include Login, Welcome, Content (eDiary Questions), and Entry 
Confirmation/Submission pages 
• Content (eDiary Questions) 
o Question #1: Worst Long COVID Pain (24-hour recall) 
▪ Rate your worst Long COVID pain intensity during the last 24 hours 
on a scale from 0-10, where 0 is NO PAIN and 10 is PAIN AS BAD 
AS YOU CAN IMAGINE. 
• Patient selects a response by moving the 0-10 point slider to 
the appropriate whole number score 
o Question #2: Sleep Quality (24-hour recall) 
▪ Rate your sleep quality last night on a scale from 0-10, where 0 is the 
BEST POSSIBLE SLEEP and 10 is the WORST POSSIBLE SLEEP 
• Patient selects a response by moving the 0-10 point slider to 
the appropriate whole number score 
o Question #3 (Post-Randomization): Study Drug  
▪ Did you take your study drug last night? 
• Patient selects yes or no 
o Question #4 (Post-Randomization): Study Drug  
▪ How many tablets of study drug did you take last night? 
• Patient selects 0, 1, or 2 
• Entry Confirmation/Submission 
o A summary page is displayed showing the patient’s entries for each question 
o Please confirm your answers below 
▪ Pain: __ 
▪ Sleep: ___ 
▪ Medication Taken: ___  
▪ Tablets Taken: ___ 
o If all entries are correct the patient will press submit.  
o If the patient needs to revise their entries, they can press the back button to 
re-do. 
 
 
 

SAP_001.pdf: 
 
 
Statistical Analysis Plan 
 
 
Protocol Title: TNX-CY-PA201 
A Phase 2, 14-week Double-Blind, Randomized, Multicenter, Placebo- 
Controlled Study to Evaluate the Efficacy and Safety of TNX-102 SL Taken 
Daily at Bedtime in Patients with Multi-site Pain Associated with Post- 
Acute Sequelae of SARS-CoV-2 Infection (PASC) 
Protocol Number: Protocol No. TNX-CY-PA201, Amendment 02 (13 October 2022) 
Investigational 
Product: 
TNX-102 SL (cyclobenzaprine HCl sublingual tablets) 
Phase: 2 
Sponsor: Tonix Pharmaceuticals, Inc. 
 
 
SAP Author(s): 
 
 
 
SAP Version: Version 1.1 
SAP Date: 20JUL2023 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 1 
20JUL2023 


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DOCUMENT HISTORY 
 
Version 
Date 
Author 
Description 
1.0 
07JUN2023 
 
Final 
1.1 
20UL2023 
 
 
 
orrected analysis method for ISI and 
PCFS to ANCOVA. 


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SIGNATURE PAGE AND APPROVALS 
 
 
 
 
 
Approved: 
 
 
 
 
 
Approved: 


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TABLE OF CONTENTS 
DOCUMENT HISTORY................................................................................................... 2 
SIGNATURE PAGE AND APPROVALS ....................................................................... 3 
TABLE OF CONTENTS ................................................................................................... 4 
ABBREVIATIONS ............................................................................................................ 7 
1. 
BACKGROUND..................................................................................................... 8 
2. 
OVERVIEW ........................................................................................................... 9 
3. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 10 
3.1 
Study Objectives ........................................................................................ 10 
3.1.1 Primary Objective .......................................................................... 10 
3.1.2 Secondary Objectives ..................................................................... 10 
3.2 
Study Endpoints ......................................................................................... 10 
3.2.1 Efficacy Endpoints ......................................................................... 10 
3.2.2 Secondary Endpoints ...................................................................... 10 
3.2.3 Exploratory Endpoints.................................................................... 10 
3.2.4 Safety Endpoints ............................................................................ 12 
4. 
OVERALL STUDY DESIGN AND PLAN ........................................................ 13 
4.1 
Selection of Study Population .................................................................... 14 
4.2 
Method of Treatment Assignment and Randomization .............................. 14 
4.3 
Treatment Blinding .................................................................................... 15 
4.4 
Minimization of Missing Data ................................................................... 15 
4.4.1 Opioid Usage .................................................................................. 15 
4.4.2 Intermittent Missing Data ............................................................... 16 
5. 
ANALYSIS AND REPORTING ......................................................................... 16 
6. 
SAMPLE SIZE DETERMINATION ................................................................. 16 
7. 
ANALYSIS POPULATIONS .............................................................................. 17 
8. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ................................... 18 
8.1 
General Statistical Methodology ................................................................ 18 
8.1.1 Study Success, Adjustments for Multiplicity and Other Alpha Control 
. ....................................................................................................... 18 
8.1.2 Data Handling for Patients Who Withdraw/Drop Out from the Study 
. ....................................................................................................... 19 
8.1.3 Imputation of Missing Data............................................................ 20 


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8.2 
Efficacy Assessments ................................................................................. 21 
8.2.1 Weekly Average of Daily Worst Long COVID Pain Intensity Score 
. ....................................................................................................... 21 
8.2.2 Weekly Average of Daily Sleep Quality Score .............................. 23 
8.2.3 Modified Michigan Body Map ....................................................... 23 
8.2.4 Sheehan Disability Scale ................................................................ 25 
8.2.5 PROMIS Scales .............................................................................. 25 
8.2.6 Patient Global Impression of Change (PGI-C)............................... 25 
8.2.7 Post-COVID-19 Functional Status (PCFS) scale ........................... 26 
8.2.8 Insomnia Severity Index (ISI) – Patient version ............................ 26 
8.2.9 Epworth Sleepiness Scale (ESS) .................................................... 26 
8.3 
Safety Endpoints ........................................................................................ 27 
9. 
STUDY PATIENTS AND DEMOGRAPHICS ................................................. 28 
9.1 
Disposition of Patients and Withdrawals ................................................... 28 
9.2 
Protocol Violations and Deviations ............................................................ 28 
9.3 
Demographics and Other Baseline Characteristics ..................................... 28 
10. 
EFFICACY ANALYSES ..................................................................................... 29 
10.1 
Primary Efficacy Analysis ......................................................................... 29 
10.1.1 Estimand ......................................................................................... 29 
10.1.2 Primary Analysis ............................................................................ 29 
10.1.3 Sensitivity Analysis ........................................................................ 29 
10.2 
Secondary and Exploratory Efficacy Analyses .......................................... 30 
10.2.1 Continuous Key Secondary Endpoints ........................................... 30 
10.2.2 Other Continuous Secondary and Exploratory Endpoints .............. 30 
10.2.3 Categorical Endpoints .................................................................... 32 
10.3 
Subgroup Analyses ..................................................................................... 32 
11. 
SAFETY AND TOLERABILITY ANALYSES................................................. 33 
11.1 
Adverse Events ........................................................................................... 33 
11.1.1 Adverse Events Leading to Discontinuation of Study Drug .......... 34 
11.1.2 Serious Adverse Events .................................................................. 34 
11.1.3 Oral TEAEs .................................................................................... 34 
11.1.4 Deaths ............................................................................................. 34 
11.2 
Clinical Laboratory Evaluations ................................................................. 34 


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11.3 
Columbia Suicide Severity Rating Scale (C-SSRS) .................................. 34 
11.4 
Vital Signs .................................................................................................. 35 
11.5 
Physical Examination and Oral Cavity Exam ............................................ 35 
12. 
MEDICATIONS ................................................................................................... 36 
12.1 
Concomitant Medication ............................................................................ 36 
12.2 
Opioid Medications .................................................................................... 36 
12.3 
Exposure and Compliance .......................................................................... 36 
13. 
CHANGES FROM PLANNED ANALYSIS ..................................................... 38 
14. 
REFERENCES (AVAILABLE UPON REQUEST) ......................................... 39 
15. 
APPENDICES ...................................................................................................... 40 
15.1 
Appendix A ................................................................................................ 40 
15.2 
Appendix B ................................................................................................ 41 
15.3 
Appendix C ................................................................................................ 42 
15.4 
Appendix D ................................................................................................ 43 
15.5 
Appendix E ................................................................................................ 45 


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ABBREVIATIONS 
 
ABBREVIATION 
DEFINITION OR DESCRIPTION 
AE 
Adverse Event 
BMI 
Body Mass Index 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DDFM 
Denominator degrees of freedom 
ESS 
Epworth Sleepiness Scale 
ET 
Early Termination 
FDA 
Food and Drug Administration 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
ISI 
Insomnia Severity Index 
ITT 
Intent-to-Treat 
LOE 
Loss of efficacy 
MAR 
Missing at random 
MBM 
Michigan Body Map 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing not at random 
N 
Number of patients 
NRS 
Numeric Rating Scale 
PASC 
Post-Acute Sequelae of SARS-CoV-2 Infection 
PCFS 
Post-COVID-19 Functional Status 
PGI-C 
Patient Global Impression of Change 
PROMIS 
Patient Reported Outcomes Measurement Information System 
REML 
Restricted Maximum Likelihood 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS 
Severe acute respiratory syndrome 
SD 
Standard Deviation 
SDS 
Sheehan Disability Scale 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
TNX-102 SL tablets Cyclobenzaprine HCl Sublingual Tablets 
WHO 
World Health Organization 
WHO-DD 
World Health Organization – Drug Dictionary 


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1. BACKGROUND 
This Statistical Analysis Plan (SAP) for Protocol No. TNX-CY-PA201/Prevail Study has been 
written based on the protocol and taking into account recent Food and Drug Administration (FDA) 
feedback and expectations for pain trials. 


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2. OVERVIEW 
This SAP describes the planned analysis and reporting for Protocol TNX-CY-PA201 (A Phase 2, 
14-week Double-Blind, Randomized, Multicenter, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of TNX-102 SL Taken Daily at Bedtime in Patients with Multi site Pain 
Associated with Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)). 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA, European Medicines Agency, 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. 
In preparing this SAP (Version 1.1 dated 20JUN2023), the following documents were reviewed 
in addition to the literature references cited in this SAP: 
 
 
 
 
 
 
 
 
 
 
 
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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3. STUDY OBJECTIVES AND ENDPOINTS 
3.1 Study Objectives 
3.1.1 Primary Objective 
The primary objective is to evaluate the efficacy of TNX-102 SL 5.6 mg daily at bedtime in the 
treatment of patients with multi-site pain associated with Long COVID. 
3.1.2 Secondary Objectives 
The secondary objective is to evaluate the safety and tolerability of TNX-102 SL 5.6 mg daily at 
bedtime in the treatment of multi-site pain associated with Long COVID. 
3.2 Study Endpoints 
3.2.1 Efficacy Endpoints 
The primary efficacy endpoint is: 
• Change from Baseline in the diary NRS weekly average of daily self-reported worst Long 
COVID pain intensity scores at the Week 14 endpoint 
3.2.2 Secondary Endpoints 
 
Key secondary efficacy endpoints include: 
• Change from Baseline in the weekly average of the daily diary NRS assessment of sleep 
quality at the Week 14 endpoint 
• Change from Baseline in the PROMIS score for fatigue at the Week 14 endpoint 
• Change from Baseline in the PROMIS score for cognitive function at the Week 14 
endpoint 
Other secondary efficacy endpoints include: 
• Change from Baseline in the Patient Reported Outcomes Measurement Information 
System (PROMIS) score for sleep disturbance at the Week 14 endpoint 
• Proportion of patients with a Patient Global Impression of Change (PGI-C) rating of 
“very much improved” or “much improved” at the Week 14 endpoint 
• Change from Baseline to Week 14 in the Sheehan Disability Scale (SDS) 
• Change from Baseline to Week 14 in the Insomnia Severity Index (ISI) 
• Change from Baseline to Week 14 in the Epworth Sleepiness Scale (ESS) 
 
 
3.2.3 Exploratory Endpoints 
Exploratory efficacy endpoints include: 


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• Proportion of patients with a ≥ 30% improvement from Baseline to Weeks 1−14 in the 
daily self-reported worst Long COVID pain intensity score 
• Proportion of patients with a ≥ 50% improvement from Baseline to Weeks 1−14 in the 
daily self-reported worst Long COVID pain intensity scores 
• Proportion of Patients with a PGI-C rating of “very much improved” or “much 
improved” at each post-randomization clinic visit 
• PGI-C (1-7) rating at each post-randomization clinic visit 
• Change from Baseline in the PROMIS score for sleep disturbance at each 
post-randomization clinic visit 
• Change from Baseline in the PROMIS score for fatigue at each post-randomization clinic 
visit 
• Change from Baseline in the PROMIS fatigue symptom questions 1,3,4 (individually and 
summed) at each post-randomization clinic visit 
• Change from Baseline in the PROMIS fatigue impact questions 6,7,8 (individually and 
summed) at each post-randomization clinic visit 
• Change from Baseline in the PROMIS score for cognitive function at each 
post--randomization clinic visit 
• Change from Baseline in the weekly average of the daily diary assessment of sleep 
quality at Weeks 1−14 
• Change from Baseline in the weekly average of the daily diary assessment of worst pain 
intensity scores at Weeks 1−14 
• Change from Baseline in laboratory markers of inflammation 
• Change from Baseline to Week 14 in the Post-COVID-19 Functional Status Scale (PCFS) 
• Change from Baseline in the total number of the modified Michigan Body Map pain 
regions identified as having pain at each post-randomization clinic visit 
• Change from Baseline in average NRS Long COVID pain intensity across the 7 pain 
regions in modified Michigan Body Map at each post-randomization visit; regions 
without pain identified will be assigned a value of 0 
• Change from Baseline in average NRS Long COVID pain intensity within the index site 
region on the modified Michigan Body Map at each post-randomization visit 
• Change from Baseline in average NRS Long COVID pain intensity within the worst 
region for a given visit on the modified Michigan Body Map at each post-randomization 
visit; this will compare the value for the worst region at a visit and the worst region at 
baseline 
• Subgroup analyses of the above endpoints by severity of their SARS-CoV-2 infection 
using groupings of the WHO ordinal scale of COVID severity as data allow 


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• Subgroup analyses of the above endpoints by COVID vaccine status 
 
 
3.2.4 Safety Endpoints 
Safety is assessed by the monitoring and recording of Adverse Events (AEs), clinical laboratory 
tests, vital signs, and physical examinations including examinations of the oral cavity, as well as 
the monitoring of suicidality using the Columbia Suicide Severity Rating Scale (C-SSRS). 


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4. OVERALL STUDY DESIGN AND PLAN 
This is a Phase 2, randomized, parallel-group, double-blind, placebo-controlled, 14-week study 
designed to evaluate the efficacy and safety of TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) taken 
once daily at bedtime for the management of multi-site pain associated with Long COVID. The 
study is to be conducted at approximately 30 investigational sites in the US. 
The study will consist of a Screening Visit (Visit 1, Days -35 to -8), a Washout and Screening 
period of at least 7 days (for those patients not requiring washout) and no more than 35 days, 
inclusive of a 7-day baseline data collection phase immediately preceding the Baseline Visit. 
Eligible patients who provide written informed consent will have study assessments performed at 
Screening. Due to limitations in the diary completion window, patients who are planning on 
international travel during the study period should not be considered for the study. Patients 
whose employment involves overnight shifts also should not be considered for the study due to 
the restricted completion window and the requirement for consistent bedtime dosing. 
At Screening Visit 1 and after signing the written informed consent, any required washout should 
be discussed with the patient and plans made for an appropriate schedule for reducing/stopping 
any excluded medications. This down-titration and discontinuation of excluded medications must 
be accomplished so that the patient is free of excluded medications for at least 14 days prior to 
beginning of the collection of Baseline diary data that takes place during the 7 days leading up to 
the Baseline/Randomization Visit. Any additional time required for down-titration would be in 
addition to this washout requirement. For extenuating circumstances, the total duration of the 
Screening period may be increased to up to a maximum of 49 days with Medical Monitor 
approval. All excluded medications will be stopped during the Washout period through the 
Week 14/ Early Termination (ET) Visit (Visit 6). 
Patients will be trained on use of an eDiary system at Visit 1. 
During the 7-day run-in Phase (7 days immediately preceding Visit 2 [Baseline/Randomization 
Visit; Day 1]) patients will be asked to record their worst daily Long COVID pain intensity on 
the 11-point (0−10) NRS scale using 24-hour recall and assess sleep quality from the previous 
evening, also using an 11-point NRS scale. The average of the 7 days immediately preceding 
Visit 2 (Baseline Randomization Visit; Day 1) will serve as the Baseline pre-treatment scores. 
After completing any required washout of excluded therapies and recording Baseline Diary 
scores for at least 7 days, patients will return to the investigative site for Baseline assessments 
and randomization (Day 1, Visit 2), when they will be randomly assigned to receive 
TNX-102 SL or matching placebo sublingual tablets in a 1:1 ratio. 
During the treatment phase, each evening, the system will prompt the patient to reflect on the 
past 24 hours and record their worst pain intensity, assess their sleep quality from the previous 
evening, and log study drug dosing from the previous night (post -randomization). 
Patients will take the study drug SL once daily at bedtime, starting on the day of randomization 
(Day 1), for 14 weeks. For the first 2 weeks of treatment, patients will start on TNX-102 SL 
2.8 mg/day (1 tablet) or placebo. Patients will continue to record their worst daily pain, assess 
their sleep quality from the previous evening, and log study drug compliance. 


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All patients will then return to the clinic at Week 2 (Visit 3) for efficacy and safety assessments 
and assessment of study drug compliance. The study drug dose will be increased to 2 tablets 
(5.6 mg; 2 x 2.8 mg TNX-102 SL tablets or placebo) or 2 placebo tablets taken SL and 
simultaneously daily at bedtime. Patients will next return to the clinic at Week 6 (Visit 4) for 
assessment of safety, efficacy, study drug compliance, and dose tolerability at the 5.6-mg dose. 
In scenarios in which TNX-102 SL 5.6 mg (or 2 placebo tablets) is considered intolerable due to 
adverse event(s) (AEs) and would otherwise lead to study discontinuation, with Medical Monitor 
approval, the Investigator may lower the daily dose to 1 tablet every night (TNX-102 SL 2.8 mg 
or 1 placebo tablet). If/when it is deemed clinically warranted by the Investigator, rechallenge 
with 2 tablets TNX-102 SL 2.8 mg (5.6 mg dose)/placebo may be attempted or the patient may 
remain on the lower dose for the remainder of the study. It will be emphasized to Investigators 
that such dosage reduction should only be considered when the patient’s intolerability is 
sufficient to cause the patient to consider discontinuing from the study. It will be emphasized to 
participating patients that they should only make changes in study drug dose upon consultation 
with the Investigator, and they should notify the clinic immediately if they think the dosage 
needs to be adjusted. Ideally, any changes in dose should only be made at a scheduled visit, but, 
if it necessary to change dose between visits, the change should only be made upon the 
recommendation of the Investigator after discussion between the patient and the Investigator. 
Patients will return to the clinic for safety, tolerability, and efficacy assessments, and 
assessments of study drug compliance at Week 2 (Visit 3), Week 6 (Visit 4), Weeks 10 (Visit 5) 
and 14 (Visit 6) or ET. 
Approximately 2 weeks after Week 14 (Visit 6), there will be a Post-study Safety Follow-up 
telephone call (Visit 7), and approximately 4 weeks after Week 14, there will be a 1-Month 
Post-study Safety Follow-up telephone call (Visit 8). 
Due to the exceptional circumstances caused by the COVID-19 pandemic, an option for a 
telephone visit will be available for Weeks 2, 6, 10 (Visits 3, 4, 5), and, only with Medical 
Monitor approval, Week 14/Visit 6 (or ET) for those unable to attend an in-clinic visit due to the 
COVID-19 pandemic. However, all visits should be conducted in person whenever possible. 
The total duration of the study, including screening and follow-up, may be as long as 25 weeks. 
The maximum treatment duration will be 14 weeks. 
Patients who wish to withdraw from the study may do so at any time. 
4.1 Selection of Study Population 
For a complete list of inclusion and exclusion criteria please refer to the study protocol. 
4.2 Method of Treatment Assignment and Randomization 
The following randomization criteria must be satisfied at the Baseline visit (Visit 2) to be eligible 
for randomization: 
 
1. Continues to meet all inclusion and exclusion criteria, including urine and blood test 
results, and is successfully and consistently utilizing the diary system. 
2. Patient’s pain satisfies the following criteria, as assessed by diary pain scores (24-hour 
recall): 


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a. A mean worst daily Long COVID pain intensity score ≥ 4 and ≤ 9 on the 11-point 
(0−10) NRS for the 7 days immediately preceding Visit 2, and 
b. No more than 2 individual days with a Long COVID pain score < 4 on the 7 days 
immediately preceding Visit 2, and 
c. No score of 10 on any of the 7 days immediately preceding Visit 2, and 
d. Long COVID pain scores recorded on at least 5 out of the 7 days immediately 
preceding Visit 2 
 
Patients will be randomly assigned to receive TNX-102 SL or matching placebo sublingual tablet 
in a 1:1 ratio. 
4.3 Treatment Blinding 
This is a double-blind study. Unless otherwise specified, all study personnel are to remain 
blinded to study drug. Treatment assignments will not be revealed until all patients have 
completed the study and the database has been finalized and closed. 
If AEs occur that are considered to be intolerable, the investigator must decide whether it is 
necessary for the patient to discontinue study drug; however, the investigator should not be 
unblinded unless it is imperative for the patient’s overall safety to determine whether the patient 
received active study drug (e.g., in the event of overdose). 
4.4 Minimization of Missing Data 
The Sponsor believes it has incorporated strong steps into the study design to ensure 
minimization of missing data during the treatment period. Multiple analysis techniques to 
examine the impact of missing data on the robustness of results will be carried out. Additionally, 
if the patient reports intolerable side effects that are likely to result in premature discontinuation 
from the study, then the dose of study drug may be reduced to 1 tablet sublingually nightly, with 
Medical Monitor approval. Any reduction in study drug dose must be documented in the case 
report form (CRF). The goal is for the patient to be on a stable and final dose of study drug 
starting from the Week 2 Visit, at the highest dose tolerated (preferably 2 tablets daily at 
bedtime). It is anticipated that only a small portion of patients will require dosage reduction, as 
TNX-102 SL 5.6 mg has been well-tolerated in previous Phase 3 studies of TNX-102 SL. 
Moreover, the gradual titration from 1 tablet for the first 2 weeks to 2 tablets for the remainder of 
the study should help with acclimation to the higher dose. 
4.4.1 Opioid Usage 
In order to minimize confounding issues related to concomitant usage of opioids, investigators 
have been asked to identify candidates for this clinical trial that are not currently using chronic 
opioids. However, it is understood by the Sponsor that opioid usage is sometimes unavoidable 
for acute conditions. In the event that an opioid is required for the management of an acute pain 
condition, the patient will be instructed to contact the site immediately so that appropriate 
management decisions can be implemented and accurate medication records obtained. In 
addition, when feasible, study visits may be delayed to avoid the contamination of data by recent 


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opioid usage. At a minimum, no opioid/narcotic should be utilized within 2 days of a study visit, 
and ideally there will be no usage during the 7 days prior to any visit. 
4.4.2 Intermittent Missing Data 
Intermittent missing daily data will not be imputed and weekly averages will be calculated using 
available values, even if only a single value is available for a week. Intermittent missing data 
(weekly averages and/or in-clinic assessments) occurring prior to discontinuing use of study drug 
is assumed to be missing at random, and analyses have been chosen to mitigate the impact of 
these missing data (Section 10.1). 
5. ANALYSIS AND REPORTING 
All final, planned analyses will be performed after the last patient has completed the last study 
visit and end-of-study assessments and all relevant study data have been processed and 
integrated into the analysis data base. Any post-hoc, exploratory analyses completed to support 
planned study analyses, but which were not identified in this SAP, will be documented and 
reported in appendices to the CSR. Any results from these unplanned analyses (post-hoc) will 
also be clearly identified as such in the text of the CSR. 
6. SAMPLE SIZE DETERMINATION 
The study is planned to enroll approximately 470 patients total in a 1:1 randomization, that is, 
235 patients in each of the TNX-102 SL and placebo arms. Using a two-sided t-test with an alpha 
level of 0.05, a sample size of 235 per group provides a power of approximately 90% if the effect 
size is 0.3. 


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7. ANALYSIS POPULATIONS 
In the case that the study goes to full enrollment or has a sample size increase, the following 
analysis populations are planned for this study: 
• All Patients: used for summaries of dispositions of patients; tabulations of dispositions 
may also use the populations below. 
• Safety population: all patients who receive at least one dose of the investigational 
product. All safety analyses will be performed using this population, analyzed as treated. 
• Intention-to-treat (ITT) population: all patients who are randomized and have at least one 
post-baseline daily diary entry. This is the primary population for efficacy analyses, and 
patients will be analyzed based on their randomized treatment. 


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8. GENERAL ISSUES FOR STATISTICAL ANALYSIS 
8.1 General Statistical Methodology 
Descriptive summaries will be provided where appropriate for each of the primary and secondary 
variables. In general, tables will summarize data by treatment group and visit. All patients for a 
population in each treatment group will be grouped together; patients that reduce dose from two 
tablets per day to one tablet per day will be not be reported separately for the analyses described 
in this SAP, unless otherwise noted. If there are more than 10 patients in the active arm with a 
dose reduction at any point in the study, summary statistics on key outcomes may be reported for 
patients with dose reductions. 
Baseline characteristic and safety tables will be completed for the Safety Population unless 
otherwise specified. Efficacy tables will be presented for the ITT Population. 
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. 
Baseline values are defined as the last non-missing measurement prior to the first dose of study 
drug. For scores obtained via diary, baseline will be defined as the average of the scores from 
the 7 days prior to the baseline visit. 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, Adjustments for Multiplicity and Other Alpha Control 
8.1.1.1 Study Success 
 
If the effect size observed for the primary 
analysis is greater than 0.20, the trial will be considered to have achieved proof of concept and 
would support further research of the product in this indication. 
In the event that statistical significance for the primary is achieved, the multiplicity algorithm 
below will apply. If statistical significance is not obtained, but proof of concept is declared on 
the primary, there will be no formal hierarchy or thresholds subsequently considered for 
secondary endpoints. 


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8.1.1.2 Multiplicity 
To adjust for multiplicity and to control for overall type I error, a sequential test procedure will 
be applied to the primary and key secondary efficacy endpoints. If the primary analysis produces 
a result that is statistically significant at the two-sided 0.05 level, a significance level of 0.05 will 
be used for comparing the key secondary endpoints in an ordered fashion. If the analysis for a 
key secondary endpoint does not produce a statistically significant result, then the remaining key 
secondary endpoint analyses will automatically be considered non-significant regardless of the p- 
value produced. 
The order of key secondary endpoints in which they are to be tested is as follows: 
• Change from Baseline in the weekly average of the daily diary NRS assessment of sleep 
quality at the Week 14 endpoint 
• Change from Baseline in the PROMIS score for fatigue at the Week 14 endpoint 
• Change from Baseline in the PROMIS score for cognitive function at the Week 14 
endpoint 
No other adjustments for multiplicity will be made and other p-values displayed in the output 
will be considered for descriptive summary purposes only and will not be used for formal 
inference. Additional details regarding statistical analysis for the listed endpoints can be found 
in Section 10. 
 
 
8.1.2 Data Handling for Patients Who Withdraw/Drop Out from the Study 
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 (Week 2, 6, 10, 14) where 
the given data are collected, using midpoints between visits to window the early termination. If 
this results in two records for a given visit, then the one closest to the targeted date will be used. 
For example, a patient with valid Week 10 clinic assessment collected on Day 72 that has early 
termination data collected on Day 79, would have the early termination data mapped to Week 10; 
however, since Day 72 data is present and closer to the target date, it would be analyzed and the 
Day 79 data would be excluded. A patient without valid Week 10 data who early terminates on 
Day 79 would have the Day 79 data analyzed with the Week 10 data. 
Patients who provide 14 weeks of diary pain data will be analyzed as completers for purposes of 
the primary analysis, even if for some reason they are unable to attend a Week 14 final study 
visit. As a specific example, a patient who successfully provides 14 weeks of diary data as 
described in Section 8.2.1, but who is unable to attend a final study visit during the required time 
window because of travel or other circumstances, would be analyzed as a completer for purposes 
of the primary endpoint, but would be missing non-diary based secondary outcome measures at 
the Week 14 endpoint. For safety data, the last observation available will be summarized in 
addition to the presentation above (grouping ET visits with the closest planned visit); this will 
combine the ET visit data with the completers’ Week 14 data, regardless of when the ET 
occurred. 


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8.1.3 Imputation of Missing Data 
For individual daily pain scores, since a mean is used in the calculation of the primary endpoint, 
it is not necessary to replace values missing on random intermittent days; weeks will have 
average values as long as a single value for that week is present. 
For the primary analysis, no missing values will be imputed; a sensitivity analysis may be 
performed using the following imputation algorithm: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daily sleep diary data may be handled in an identical manner to the pain scores. 
Continuous outcomes included in the list of key secondary outcomes that are collected in-clinic 
may be handled as above, minus the step of creating weekly averages of daily values and with 
steps being done by visit instead of week. 
Patients with missing PGI-C at a given visit will be considered non-responders at that visit for 
the purposes of treatment comparisons; additional tabulations will summarize the number and 


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percentage in each category out of non-missing values as well as a count of the missing values. 
30% and 50% responders will be handled similarly with missing values being imputed as non- 
responders. 
No missing safety data will be imputed. 
8.2 Efficacy Assessments 
8.2.1 Weekly Average of Daily Worst Long COVID Pain Intensity Score 
The daily eDiary is an important aspect of this study, and all patients must receive training 
explaining what is being asked of them, when to complete the diary, and how to use the diary 
system effectively. Patients will be trained on use of the diary system at Visit 1. Additionally, 
patients should complete the training on accurate pain reporting and placebo response reduction 
training as required. 
During the 7-day run-in Phase (7 days immediately preceding Visit 2 [Baseline/Randomization 
Visit; Day 1]) patients will be asked to record their worst daily Long COVID pain intensity on 
the 11-point (0−10) NRS scale using 24-hour recall and to assess sleep quality from the previous 
evening, also using an 11-point NRS scale. The average of the 7 days immediately preceding 
Visit 2 (Baseline Randomization Visit; Day 1) will serve as the Baseline pre-treatment scores. 
During the treatment phase, each evening, the system will prompt the patient to reflect on the 
past 24 hours and record their worst pain intensity, assess their sleep quality from the previous 
evening, and log study drug dosing from the previous night (post -randomization). 
Patients will receive instructions and a password that uniquely identifies them when they log into 
the diary system, along with instructions about what to do if they have difficulty completing the 
diary. 
The diary should be started the evening of Visit 1 and completed daily until Visit 6 (Week 14). 
Patients should be instructed to complete the diary in the evening before dosing. Once the patient 
has properly identified themselves, the diary will prompt answers to the following: 
• Rate your worst Long COVID pain intensity during the last 24 hours on a scale from 
0-10, where 0 is “no pain” and 10 is “pain as bad as you can imagine”. Rate your 
sleep quality last night on a scale from 0−10 where 0 is the “best possible sleep” and 
10 is the “worst possible sleep”. 
After randomization to study drug at Visit 2, the following questions will be added to the daily 
diary (starting in the evening of the day after randomization, Day 2): 
• Did you take your study drug last night? (Yes/No) 
• If yes, how many tablets of study drug did you take last night? (1 tablet/2 tablets) 
These daily values will be averaged into a weekly mean; since a mean is used in the calculation 
of the primary endpoint, it is not necessary to replace values missing on random intermittent 
days. 
As described above, the baseline pain score will be defined as the average of the pain scores 
from the 7 days prior to the baseline visit. Pain scores must be recorded on at least 5 out of the 7 


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days immediately preceding the baseline visit in order for the patient to qualify for 
randomization. 
The mean of the daily, patient self-reported, 24-hour recall, pain severity scores for the 7 days of 
each week will serve as the pain score for that study week. All available values will be used; if a 
patient has at least one value for the week, the week is non-missing. Because there is a -4 day 
and +7 day window around the scheduling of Visit 6 (Day 99), the study weeks will be anchored 
by the timing and completeness of their final study visit. Ideally, patients appearing in-clinic on 
Day 99 (defining randomization as Day 1), would have last filled out their diary on Day 98; 
therefore, “Week 14” would include Days 92-98; the protocol-defined window allows visit 6 as 
early as Day 95, resulting in a nominal “Week 14” including Days 88-94. Likewise, patients 
may appear in-clinic per protocol as late as Day 106, resulting in a “Week 14” interval running 
from Day 99-105. 
Due to impacts from the COVID-19 pandemic, the criteria for calculating the Week 14 average 
will be marginally relaxed beyond the protocol-specified visit windows to allow for additional 
flexibility by permitting data collected during Week 13 to be used to calculate the Week 14 
average: working backwards from Day 98, the first non-missing day (as early as Day 91) will 
serve as the LAST day of Week 14 for the purpose of anchoring and any non-missing values in 
the 6 days prior to that day will contribute to the average. If a patient does not have a non- 
missing value on/after Day 91, any available data from Day 85-91 will be averaged as Week 14 
and Day 91 will serve as the anchor. Patients without data on/after Day 85 will be missing for 
Week 14 and handled as described below. Specific examples of calculating the Week 14 pain 
score are described in Appendix D. 
Each week prior to Week 14 will be based on 7-day intervals; depending on the interval selected 
for “Week 14”, this will result in Week 1 having less than 7 days or some “extra” days prior to 
Week 1. Extra days will be dropped and not included in the analysis; in the case of less than 7 
days, the available days will be averaged, as long as there are non-missing values. The earliest 
day included in the Week 1 average will be the data entered the day after randomization 
(covering roughly the 24 hours following their first dose of study drug). 
For patients who withdraw from the study early, that do not have a final study visit or complete 
the study but do not have data in the 7 days preceding their last visit, the last day of diary data (at 
or prior to Day 106) will serve as the anchor point for dividing the available data into weeks. 
First, the nearest nominal end day for a weekly period is identified and this week will be the 
assigned the data from the 7 days immediately preceding the anchor date. For example, if a 
patient early terminates on study Day 24, the Week 3 (nominally ending on day 21) average will 
be based on the 7 days prior to Day 24 (Days 17-23). Lost to follow-up patients that continue to 
fill out the diary into Week 14 and beyond will have non-missing values for the Week 14 time 
point for diary outcomes (as well as any prior weeks for which data are present). Day 106 will 
be the last allowable day to be included in the average. 
 
Nominal Study 
 
Week 
 
Day Intervals 
 
Baseline 
Day -7 to -1 


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Day of 
Randomization 
Week 1 
 
Day 1 
Day 2 to 7 
Week 2 
Day 8 to 14 
Week 3 
Day 15 to 21 
Week 4 
Day 22 to 28 
Week 5 
Day 29 to 35 
Week 6 
Day 36 to 42 
Week 7 
Day 43 to 49 
Week 8 
Day 50 to 56 
Week 9 
Day 57 to 63 
Week 10 
Day 64 to 70 
Week 11 
Day 71 to 77 
Week 12 
Day 78 to 84 
Week 13 
Day 85 to 91 
 
Week 14 
Day 92 to 98 
 
 
Change from baseline will be defined as the pain score at each week minus the baseline pain 
score (with baseline and weekly pain scores derived as described above). Thus, negative 
changes will denote lesser pain and larger negative values will denote greater improvement. 
8.2.2 Weekly Average of Daily Sleep Quality Score 
The weekly average of daily sleep quality score will be obtained in the same manner as the 
weekly average of the daily worst long COVID pain intensity score, via electronic Interactive 
Response Technology (IRT) system. Derivation of the weekly average sleep quality scores and 
censoring of data will be treated the same as the weekly average pain scores described in Section 
8.2.1, using the same windows based on the date of collection. It should be noted that the sleep 
prompt asks about the prior night’s sleep; thus, patients report their sleep starting the first night 
that they take randomized drug through the night between day 97-98, if their final visit is day 99. 
As with pain, negative changes will denote improvement in sleep quality and larger negative 
values will denote greater improvement. 
8.2.3 Modified Michigan Body Map 
The Michigan Body Map (MBM) is based on the 2011 FM Survey Criteria, a tool that is 
commonly used to assess for the presence of multi-site pain in fibromyalgia (FM), a disorder 
characterized by widespread body pain, along with comorbid symptomatology similar to that 
experienced by patients with Long COVID. The 2011 FM Survey Criteria include the assessment 
of pain in 19 specific body areas using the Widespread Pain Index (WPI). The areas from the 
WPI are then combined with the Symptom Severity scale to assess the presence and severity of 
FM. The MBM is a graphic mannequin with the 19 areas from the WPI superimposed upon it in 
anatomically relevant locations. The MBM also contains 16 additional areas for more general 
use. The MBM, and its online version, have been validated in patients with chronic pain. 
Tonix Pharmaceuticals has modified the MBM (mMBM) in consultation with its authors. The 


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Two versions of the mMBM will be used in the study, the Screening version and the 
Baseline/Post-Randomization Version. The screening Version will assess a patient’s eligibility to 
enter the study, based on the number of body regions with pain and the Baseline/Post- 
Randomization Version will be used for assessment of outcomes. The two versions are described 
in more detail below. 
At screening 
At screening (Visit 1), the patient will complete the “Screening Visit” version of the mMBM 
with a 3 month look-back period, which includes: 
• 
 
 
 
 
 
 
 
Note: In order to be eligible for the study, the patient must have Long COVID pain in at least 4 
out of 7 body regions on Part 2 of the screening mMBM. 
At Baseline/Post-Randomization Visits (Visit 2-Visit 6) 
At randomization through the end of the study, the patient will complete “Baseline/Post- 
Randomization” version of the mMBM with a 7-day look-back period, which includes: 
• 
 
 
 
 
 
 
 
The region of pain that is selected as “most bothersome” at the Baseline Visit will be referred to 
as the “index site” thereafter. The “index site” will be followed from the Baseline Visit through 
V6 as a part of the exploratory analyses. Additional analyses related to the mMBM have been 
incorporated as exploratory endpoints as well. Refer to Appendix 2 of the Protocol for an exact 


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copy of the mMBM and definition of body regions. 
The following endpoints will be derived using the mMBM: 
• Change from Baseline in the total number (1-7) of the modified Michigan Body Map pain 
regions identified as having pain at each post-randomization clinic visit 
• Change from Baseline in average NRS Long COVID pain intensity across the 7 pain 
regions in the modified Michigan Body Map at each post-randomization visit; regions 
without pain identified will be assigned a value of 0 
• Change from Baseline in NRS Long COVID pain intensity within the index site region 
on the modified Michigan Body Map at each post-randomization visit 
• Change from Baseline in NRS Long COVID pain intensity within the worst region for a 
given visit on the modified Michigan Body Map at each post-randomization visit; this 
will compare the value for the worst region at a visit and the worst region at baseline 
8.2.4 Sheehan Disability Scale 
SDS is a brief self-reporting tool that rates the extent to which work/school, social life, and home 
life or family responsibilities are impaired by the symptoms on a 10-point visual analog scale. 
The 3 items can also be summed into a single dimensional measure of global functional 
impairment that ranges from 0 (unimpaired) to 30 (highly impaired). If a patient is not 
working/in school for reasons unrelated to their disease state, that item is not completed; in this 
case, the average of the two other items will be imputed for this measure when calculating the 
total score (but not for reporting on that individual measure). 
8.2.5 PROMIS Scales 
The PROMIS Short-Form Fatigue, Sleep Disturbance, and Cognitive Function – Abilities Scale 
Instruments each consist of 8 items in which responses are scored 1 to 5 for each item. Scores 
for all items are totaled to create a raw score. Each instrument will be considered invalid if 50% 
of the items are missing. If more than 50% of the items are answered, the raw total score will 
use the following formula to determine a new calculated score to account for missing items. 
 
New raw score = (Raw score / # of items answered) × # of total items 
New raw scores that are fractions are rounded up to the nearest whole number. Once a new raw 
score has been calculated, a T-score will be determined using Appendix A for Fatigue Inventory, 
Appendix B for Sleep Disturbance and Appendix C for Cognitive Function – Abilities scale. The 
T-scores will be analyzed. 
Note that items 1, 2, and 8 of the PROMIS Sleep Disturbance Instrument will need to have their 
directionality reversed for calculating the totals. 
8.2.6 Patient Global Impression of Change (PGI-C) 
PGI-C is a question completed by the patient at Weeks 2, 6, 10, and 14. The patient will rate the 
change in their Long COVID symptoms (specifically pain, sleep disturbance, fatigue, and/or 


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memory/concentration issues) on a 1-7 Likert scale, where 1 is “Very Much Improved” and 2 is 
“Much Improved”. Scores of 1 and 2 will be considered PGI-C responders, and all other scores 
will be considered non-responders for that visit. The proportion of responders in each treatment 
arm will be analyzed. Any missing PGI-C score will be considered a non-responder for that 
visit. 
8.2.7 Post-COVID-19 Functional Status (PCFS) scale 
The PCFS scale is an ordinal scale for assessment of patient-relevant functional limitations over 
time after COVID-19 infection. 
The scale rates the functional status of patients as: 
0 = No functional limitations 
1 = Negligible functional limitations 
2 = Slight functional limitations 
3 = Moderate functional limitations 
4 = Severe functional limitations 
D = Death 
Missing values will not be imputed. 
8.2.8 Insomnia Severity Index (ISI) – Patient version 
The ISI is a 7-item self-reported questionnaire assessing the nature, severity, and impact of 
insomnia. 
The usual recall period is the “last month” and the dimensions evaluated are severity of sleep 
onset, sleep maintenance and early morning awakening problems, sleep dissatisfaction, 
interference of sleep difficulties with daytime functioning, noticeability of sleep problems by 
others, and distress caused by the sleep difficulties. 
The scores range from 0 (no problem) to 4 (very severe problem) yielding a total score ranging 
from 0 to 28. The total score is interpreted as: 
0–7 = absence of insomnia 
8–14 = sub-threshold insomnia 
15–21 = moderate insomnia 22–
28 = severe insomnia 
Missing items will be imputed with the average of the non-missing items, as long as at least 4 
items are completed. 
8.2.9 Epworth Sleepiness Scale (ESS) 
The ESS is a self-administered questionnaire with 8 questions. The patient rates from 0 to 3 their 
usual chances of dosing off or falling asleep while engaged in 8 different activities. The total 
score can range from 0 to 24, with higher rating indicating higher average sleep propensity in 
daily life. 
Missing items will be imputed with the average of the non-missing items, as long as at least 4 
items are completed. 


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


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9. STUDY PATIENTS AND DEMOGRAPHICS 
9.1 Disposition of Patients and Withdrawals 
The numbers and percentage of patients screened, randomized, completing the study, and 
withdrawing from the study, along with reasons for withdrawal, will be tabulated overall and by 
treatment group. The number and percentage of patients in each analysis population will be 
reported. Additionally, the number and percentage of patients that have an investigator-directed 
dose reduction from two tablets per day to one tablet per day will be summarized. The 
disposition and withdrawal summaries will be based on all patients who have data entered into 
the database. 
9.2 Protocol Violations and Deviations 
Protocol deviations will be checked on complete data for all patients. Protocol deviations will be 
summarized by type, status as major vs minor, and by treatment group for the Safety population. 
Individual patients with protocol deviations or violations will be listed. 
9.3 Demographics and Other Baseline Characteristics 
Descriptive summaries of the demographic and other baseline characteristics will be completed 
for all enrolled patients in the study population by treatment groups, unless otherwise specified. 
Descriptive summaries of demographic and other baseline conditions will include: 
• Demographics (age, gender, race/ethnicity, height, weight, body mass index (BMI), 
family status, education, employment status, and MINI modules A, C, I, J, K, O) 
• Tobacco/nicotine, alcohol, and THC/cannabis use history 
 
Medical History will be coded using a current version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by SOC and Preferred Term using frequency counts by 
treatment group. Physical examination data, as well as findings from dedicated oral cavity 
examinations, will be presented in listings. 


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10. EFFICACY ANALYSES 
10.1 Primary Efficacy Analysis 
10.1.1 Estimand 
Population 
The analysis population will be patients with PASC as defined by the protocol 
inclusion/exclusion criteria. 
Variable 
The primary endpoint will be the change from baseline to Week 14 in the diary NRS weekly 
average of daily self-reported worst Long COVID pain intensity scores. 
Intercurrent Events 
For all intercurrent events, data will be analyzed as observed and missing data (both intermittent 
and following discontinuation) will be assumed to be missing at random. All patients that 
complete at least one diary pain entry will contribute to the model estimation. 
Population-Level Summary 
The population-level summary will be the difference in least-square means between treatment 
arms (analyzed as randomized) at Week 14 from the primary analysis model. See Section 10.1.2 
for details. 
10.1.2 Primary Analysis 
The mean change from baseline in the weekly average of daily pain scores from baseline to each 
week in the TNX-102 SL and placebo arms will be analyzed using a restricted maximum 
likelihood (REML) based repeated measures approach without imputation under the assumption 
that data are missing at random. The model will include the fixed, categorical effects of 
treatment, study week, and treatment by study week interaction, as well as the fixed covariates of 
baseline value and baseline value score-by-study week interaction. An unstructured covariance 
structure will be used to model the within-patient errors. If this analysis fails to converge, the 
following structures will be tested in this order: first order ante dependence, heterogeneous first 
order autoregressive, heterogeneous compound symmetry and compound symmetry with the first 
to give convergence used. The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom (DDFM) with the unstructured matrix; other covariance 
structures will utilize the sandwich matrix and the SAS® default DDFM. Week 14 will serve as 
the primary time point of interest. Significance testing will be based on least-squares means and 
two-sided 95% confidence intervals will be presented. The p-values will be compared against a 
two-sided alpha of 0.05. 
10.1.3 Sensitivity Analysis 
The following sensitivity analysis may be performed: 
Data will be imputed using multiple imputation as described in Section 8.1.4. Models identical to 
the primary analysis described above will be fit for the 20 MI repeated sets; LS means and 


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differences across the twenty MI reps will be combined using SAS® procedure MIANALYZE 
(Rubin, 1976). Week 14 will serve as the primary time point of interest. Significance testing will 
be based on least-squares means and two-sided 95% confidence intervals will be presented. The 
p-values will be compared against a two-sided alpha of 0.05. 
10.2 Secondary and Exploratory Efficacy Analyses 
Secondary efficacy analyses will be based on the ITT population only. 
10.2.1 Continuous Key Secondary Endpoints 
For the purposes of possible label claims and reported p-values entered into the multiplicity 
algorithm, an approach identical to the primary analysis will be used for all continuous 
outcomes. See Section 10.1.2 for the analysis approach. 
Outcomes using these analyses will include: 
• Change from Baseline in the weekly average of the daily diary NRS assessment of sleep 
quality at the Week 14 endpoint 
• Change from Baseline in the PROMIS score for fatigue at the Week 14 endpoint 
• Change from Baseline in the PROMIS score for cognitive function at the Week 14 
endpoint 
For each, all time points will be summarized, but the primary time point of interest is Week 14. 
Time points other than Week 14 are considered exploratory. The estimand for each is identical 
to the primary, substituting for the endpoint in question. 
This will be repeated on the outcomes above, but using observed data only without imputation. 
For the sleep quality assessment collected via a daily patient diary, the baseline score and the 
weekly scores for each patient will be calculated as the weekly average score based on the mean 
of the scores recorded for that study week (Section 8.2.2). 
10.2.2 Other Continuous Secondary and Exploratory Endpoints 
Descriptive statistics will be reported for each endpoint, time point and treatment for both the 
observed values and the changes from baseline. 
The with the exception of ISI and PCFS (collected just once post-baseline), change from baseline 
in each endpoint from baseline to each visit in the TNX-102 SL and placebo arms will be 
analyzed using a restricted maximum likelihood (REML) based repeated measures approach 
with no imputation. Week 14 will serve as the primary time point of interest. Models will 
include the fixed, categorical effects of treatment, study week, and treatment by study week 
interaction, as well as the fixed covariates of baseline value and baseline value score-by-study 
week interaction. An unstructured covariance structure will be used to model the within-patient 
errors. If this analysis fails to converge, the following structures will be tested in this order: first 
order ante dependence, heterogeneous first order autoregressive, heterogeneous compound 
symmetry and compound symmetry with the first to give convergence used. The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom (DDFM) with the 
unstructured matrix; other covariance structures will utilize the sandwich matrix and the SAS® 


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default DDFM. Significance testing will be based on least-squares means and two-sided 95% 
confidence intervals will be presented. 
For ISI and PCFS, an ANCOVA model will be fit on the change from baseline to Week 14. 
Fixed effects will include categorical effects for treatment and a covariate for the baseline value 
of each scale. Significance testing will be based on least-squares means and two-sided 95% 
confidence intervals will be presented. 
Secondary Efficacy Endpoints analyzed this way will include: 
• Change from Baseline to Week 14 in the Sheehan Disability Scale (SDS) 
• Change from Baseline in the Patient Reported Outcomes Measurement Information 
System (PROMIS) score for sleep disturbance at the Week 14 endpoint 
• Change from Baseline to Week 14 in the Insomnia Severity Index (ISI) 
• Change from Baseline to Week 14 in the Epworth Sleepiness Scale (ESS) 
Exploratory endpoints analyzed this way will include: 
• Patient Global Impression of Change (PGI-C) Scored 1-7 at Week 14 (without the fixed 
covariates of baseline value and baseline value score-by-study week interaction) 
• Change from Baseline in the PROMIS score for sleep disturbance at each 
post--randomization clinic visit 
• Change from Baseline in the PROMIS score for fatigue at each post-randomization clinic 
visit 
• Change from Baseline in the PROMIS fatigue symptom questions 1,3,4 (individually and 
summed) at each post-randomization clinic visit 
• Change from Baseline in the PROMIS fatigue impact questions 6,7,8 (individually and 
summed) at each post-randomization clinic visit 
• Change from Baseline in the PROMIS score for cognitive function at each 
post--randomization clinic visit 
• Change from Baseline in the weekly average of the daily diary assessment of sleep 
quality at Weeks 1−14 
• Change from Baseline in the weekly average of the daily diary assessment of worst pain 
intensity scores at Weeks 1−14 
• Change from Baseline in laboratory markers of inflammation 
• Change from Baseline to Week 14 in the Post-COVID-19 Functional Status Scale (PCFS) 
• Change from Baseline in the total number of the modified Michigan Body Map pain 
regions identified as having pain at each post-randomization clinic visit 
• Change from Baseline in average NRS Long COVID pain intensity across the 7 pain 
regions in modified Michigan Body Map at each post-randomization visit 


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• Change from Baseline in average NRS Long COVID pain intensity within the index site 
region on the modified Michigan Body Map at each post-randomization visit 
• Change from Baseline in average NRS Long COVID pain intensity within the worst 
region for a given visit on the modified Michigan Body Map at each post-randomization 
visit 
As noted above, results of Week 14 are of primary interest, with other time points being 
exploratory. For PROMIS fatigue, the questions regard symptoms and impacts will be analyzed 
independently and additional post-hoc analyses may be completed to evaluate how they 
contribute to the overall score. 
10.2.3 Categorical Endpoints 
A categorical analysis of PGI-C will compare the treatment arms with a difference in proportions 
Z test (equivalent to a Pearson’s Chi Squared). Patients with results of “very much improved” or 
“much improved” (defined as responders) will be compared to all other categories (defined as 
non-responders). Patients with missing data will be considered non-responders. The percentages 
of responders and the 95% CIs of the percentages as well as the difference in the percentages and 
its 95% CI will be reported. In the case of sparse data (<5 patients expected in a cell), Fisher’s 
exact test will be employed. A summary of frequency counts for all PGI-C responses for each 
time point will be presented; Week 14 is of primary interest and all other time points are 
considered exploratory. 
Exploratory analyses of the following endpoints will use identical methodology as the PGI-C 
analysis: 
• Proportion of patients with a ≥ 30% improvement from Baseline to Weeks 1−14 in the 
daily self-reported worst Long COVID pain intensity score 
• Proportion of patients with a ≥ 50% improvement from Baseline to Weeks 1−14 in the 
daily self-reported worst Long COVID pain intensity scores 
The number and percentage of patients in each PCFS category will be reported at each visit 
where it is collected. 
10.3 Subgroup Analyses 
Exploratory subgroup analyses of the primary, secondary and exploratory analyses may be 
performed. These may include: 
• Subgroup analyses by severity of the patients’ SARS-CoV-2 infection using groupings of 
the WHO ordinal scale of COVID severity as data allow 
• Subgroup analyses by COVID vaccine status 


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11. SAFETY AND TOLERABILITY ANALYSES 
The safety analyses will be run on the Safety population. The analysis of safety in this study will 
include summaries of the following safety and tolerability data collected for each patient: 
• Adverse Events 
• Clinical Laboratory Investigations 
• C-SSRS 
• Vital Signs 
• Physical Examinations and examinations of the oral cavity 
11.1 Adverse Events 
All AEs, TEAEs, and SAEs will be coded using a current version of the MedDRA Dictionary. 
The collection of adverse events will begin at the time the patient is consented and screened for 
the study. Treatment-emergent adverse events (TEAEs) are defined as either new onset AEs 
with an onset at the time of or following the start of treatment, as indicated by a “no” answer to 
“Did AE start prior to the first dose?”, or a recurrence of an AE (or medical history) present prior 
to randomization but increasing in severity, frequency or relationship at the time of or following 
the start of treatment. 
An AE summary table will be presented for the following: 
• All TEAEs 
• TEAEs by severity 
• TEAEs leading to study drug discontinuation 
• TEAEs by relationship 
• SAEs 
• Oral cavity TEAEs 
• Oral cavity TEAEs by severity 
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, oral 
cavity 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. 
In the AE data listings, all AEs will be displayed. AEs that occur prior to randomization will be 
considered pre-treatment AEs, and will be determined by a “yes” response to the CRF question, 
“Did the AE start prior to the first dose?” AEs that start on the date of randomization but have a 
“yes” response to this question will be categorized as pre-treatment AEs. TEAEs will be defined 
from the date of randomization and a “no” response to the CRF question, “Did the AE start prior 
to the first dose?” 


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11.1.1 Adverse Events Leading to Discontinuation of Study Drug 
A data listing of AEs leading to discontinuation of study drug will also be provided, displaying 
details of the event(s) captured on the CRF. 
11.1.2 Serious Adverse Events 
A data listing of SAEs will also be provided, displaying details of the event(s) captured on the 
CRF. 
11.1.3 Oral TEAEs 
In light of the study drug’s sublingual route of delivery, patients will undergo a detailed 
examination of the oral cavity at screening and brief examinations at all other visits. 
AEs involving the oral cavity may be spontaneously reported by the patient, observed during an 
oral cavity examination, or both. Oral cavity AEs will be identified by a “yes” response to the 
CRF question, “Is the AE in the oral cavity?” Additional information will be collected on oral 
cavity AEs (based on a “yes” response to the above question), including whether the AE occurs 
immediately or very soon after dosing, an approximation of the duration of the AE (less than or 
greater than 60 minutes), and whether the AE is still present the next morning upon awakening. 
A separate by-patient listing of oral cavity AEs (including pre-treatment oral cavity AEs) will be 
provided. 
11.1.4 Deaths 
A listing of deaths will also be provided for the Safety Population. 
11.2 Clinical Laboratory Evaluations 
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. 
A by-patient listing of all clinical laboratory (Chemistry, Hematology and Urinalysis) data will 
also be provided. 
11.3 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is an instrument that measures suicidal ideation and behavior, as represented by the 
items displayed in the table below. 
The number of patients with increase over baseline in suicidal ideation at any time point will be 
reported. The maximum ideation across all visits for a patient will also be summarized with 
counts and percentages both for all patients and among patients with an increase in ideation. 
Likewise, the count and percentage of patients with any suicidal behavior will be reported along 
with a summary of the most extreme behavior each patient reported. 
 
Category 
Items 
 
A) Suicidal Ideation 
(1) Wish to be dead 
(2) Non-specific active suicidal thoughts 
(3) Active suicidal ideation with any methods (not plan) without intent 


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B) Suicidal 
Behavior 
to act 
(4) Active suicidal ideation with any some intent to act, without 
specific plan 
(5) Active suicidal ideation with specific plan and intent 
(6) Preparatory acts or behavior 
(7) Aborted attempt 
(8) Interrupted attempt 
(9) Actual attempt 
10) Completed suicide 
Suicidal Behavior present (composite of items 6-10) 
 
Non-Suicidal Self-Injurious Behavior 
 
 
A data listing of C-SSRS results will include only patients with suicidal ideation, suicidal 
behavior, or self-injurious behavior without suicidal intent at any visit. For patients with suicidal 
ideation, suicidal behavior, or self-injurious behavior without suicidal intent at any time, data 
from all visits will be displayed. 
11.4 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline at each assessment time point and last available assessment will be 
calculated for vital signs including weight, BMI, body temperature, pulse rate, systolic blood 
pressure and diastolic blood pressure. 95% confidence intervals will be presented for change 
from baseline. 
These summaries will be presented by treatment and assessment time for the Safety population. 
ET data will be analyzed with the closest visit that does not have a valid assessment value. 
11.5 Physical Examination and Oral Cavity Exam 
A standard physical examination will be performed at Screening, Baseline, and Week 14. In 
addition, a separate examination of the oral cavity will be performed at each visit (Screening 
through Week 14). Oral cavity examination findings will be documented separately from other 
physical examination findings. Note that the oral exam did not include examination of the 
pharynx; any findings there would be recorded with the physical exam, and also on the AE page, 
if appropriate. 
A data listing of the results at each scheduled visit will be presented for both the standard 
physical examination and the examination of the oral cavity. 


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12. MEDICATIONS 
12.1 Concomitant Medication 
All medications will be coded using a current version of the World Health Organization Drug 
Dictionary. 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 Levels 1 and 3 and preferred term. 
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. 
Prior and Concomitant medications will be summarized. All medications will be presented in a 
listing. 
Please refer to Section 8.3 to impute the partial start date and end date of concomitant 
medication. 
12.2 Opioid Medications 
A list of patients’ concomitant medication records from the CRF data identifying opioid usage 
will be reviewed by the project team and approved by the sponsor prior to database lock. This 
listing will be used to flag opioid records in the analysis database and in the by- patient 
concomitant medication listings. 
12.3 Exposure and Compliance 
The treatment duration will be calculated and summarized based primarily on CRF data for first 
and last dose dates (number of days=last dose date – first dose date+1). If these values are 
missing or patients’ diary data indicate dates that exceed this period, the diary dates will be 
utilized. 
Days of exposure will be based on patients’ responses to the daily questions regarding 
medication usage. The number of days on study drug is the total number of days a patient 
responds that study drug was taken. If the CRF data for the last dose date is a date not included 
in the diary, it will be added to the count (this should be true for most completing patients since 
they do not fill out a diary the day of their last visit). The number of patients with total exposure 
by visit weeks (≤2 weeks, 2 to ≤4, 4 to ≤8, 8 to ≤12, 12 to ≤14 and >14 weeks) will be presented. 
Missing days where the patient did not complete the diary will be treated as though study drug 
was not taken. Days of exposure will also be calculated for the days on each dose of study drug. 
Additionally, the number and percentage of patients that drop back to one tablet per day will be 
summarized and the week in which they reduced their dose will be tabulated (among those that 
had a dose reduction). 
Compliance will be similarly summarized across all study visits 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 date of last diary recorded dose-randomization date +1. This compliance reporting 


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will take into account whether or not they took any medication, but will not account for the 
number of tablets they took on a given day. 
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% 
to ≤ 100%, greater than 100%) will also be presented. 
A listing of drug accountability data based on CRF data will be provided. 


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13. CHANGES FROM PLANNED ANALYSIS 
 
Consequently, a number of analyses were simplified or removed 
from the SAP that were planned in the protocol. 
• The interim analysis was removed, and the required alpha spend eliminated. 
• The imputation algorithm was removed from the primary analysis and shifted to an 
optional sensitivity analysis. As such, the ITT population was updated to include the 
requirement that patients have at least one post-baseline diary entry. 
• Lab summaries were eliminated; lab results will be presented in listings 
• C-SSRS summaries were simplified 
• Site covariate removed due to low patient counts spread over many sites 


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14. REFERENCES (AVAILABLE UPON REQUEST) 
Guidance for Industry Adaptive Design Clinical Trials for Drugs and Biologics, U.S. Department 
of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and 
Research (CDER), Center for Biologics Evaluation and Research (CBER), February 2010. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Scoring Guide. Available at 
http://cssrs.columbia.edu/scoring_cssrs.html 
PROMIS Fatigue. (2013, May 14). A brief guide to the PROMIS fatigue instruments. Retrieved 
from http://www.assessmentcenter.net/documents/PROMIS Fatigue Scoring Manual.pdf 
PROMIS Sleep Disturbance. (2013, May 14). A brief guide to the PROMIS sleep disturbance 
instruments. Retrieved from 
https://www.assessmentcenter.net/documents/PROMIS%20Sleep%20Disturbance%20Scoring% 
20Manual.pdf 
Rubin, D. B. (1976), “Inference and Missing Data,”Biometrika, 63, 581–592. 


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15. APPENDICES 
15.1 Appendix A 
 


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15.2 Appendix B 
 


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15.3 Appendix C 
 


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15.4 Appendix D 
The following conventions will be used for calculation of a patient’s nominal Week 14 score. 
All other week scores are calculated relative to the nominal Week 14 interval. 
 
Landmark 
Endpoint Visit 
Day 
Last Available 
Diary Score 
Recorded 
Days Used to 
Calculate 
“Week 14” 
Comment 
99 
98 
92-98 
Ideal condition with final study 
visit on Day 99, last diary data 
will be day 98. 
100 
99 
93-99 
101 
100 
94-100 
102 
101 
95-101 
103 
102 
96-102 
104 
103 
97-103 
105 
104 
98-104 
106 
105 
99-105 
Out of window 
(late) 
106+ 
99-105 
Since the Week 14 endpoint is 
Day 99 -4/+7 days, days after 106 
are outside the Week 14 nominal 
interval. Any scores recorded 
after day 106 will be ignored. 
98 
97 
91-97 
97 
96 
90-96 
96 
95 
89-95 
95 
94 
88-94 
94 
93 
87-93 
Out of window, but allowed 
93 
92 
85-92 
Out of window, but allowed 
92 
91 
85-91 
Out of window, but allowed 


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<92 
<91 
85+ 
Must have a valid score occurring 
on/after day 85 or will be missing 
for week 14 


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15.5 Appendix E 
The following list of numbers will be used for random seeds where required for MI processes: 
4892962 
3752934 
5798332 
3796594 
6437925 
3949255 
3597909 
3067243 
7256068 
6953553 
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 in the last by 1. All seeds used will be documented in the 
programming specifications and the programs themselves. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Intermediary Delivery Events 
Status 
Timestamp 


 


 
 
 
 
 
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