Clinical trial NCT04172831
Conditions: Fibromyalgia
Keywords: Pain Sleep Fibromyalgia FM
Sponsor: Tonix Pharmaceuticals, Inc.
Start date: 2019-12-09; Completion date: 2020-10-29
Enrollment: 503 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, 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 daily at bedtime for the treatment of fibromyalgia.

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: 
Tonix Pharmaceuticals, Inc. • 26 Main Street, Suite 101 Chatham, NJ 07928 • Tel: 862.904.8182  
 
          
 
 
 
 
 
TNX-CY-F304  
 
A PHASE 3, DOUBLE-BLIND, RANDOMIZED, 
MULTICENTER, PLACEBO-CONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF TNX-102 SL 
TAKEN DAILY AT BEDTIME IN PATIENTS WITH 
FIBROMYALGIA  
“RELIEF STUDY”  
 
 
Document Date: 27 MARCH 2020  
 
NCT04172831 




Protocol No. TNX-CY-F304 
 
CONFIDENTIAL 
Final Amendment Version 1.2 March 27, 2020 Page 2 of 89 
INVESTIGATOR’S AGREEMENT 
 
I have read the TNX-CY-F304 protocol and agree to conduct the study as outlined.  I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date 




Protocol No. TNX-CY-F304 
 
CONFIDENTIAL 
Final Amendment Version 1.2 March 27, 2020 Page 4 of 89 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Tonix Pharmaceuticals, Inc. 
Name of Investigational Product: 
TNX-102 SL (Cyclobenzaprine HCl Sublingual Tablets) 
Name of Active Ingredient: 
Cyclobenzaprine HCl 
Title of Study:  
A Phase 3, Double-Blind, Randomized, Multicenter, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of TNX-102 SL Taken Daily at Bedtime in Patients with Fibromyalgia (Protocol No. TNX-
CY-F304) 
Study center(s):  35 to 45 centers in the United States (US) 
Estimated Studied period: 14 months 
Estimated date first patient enrolled:  Nov 2019 
Estimated date last patient completed: Dec 2020 
 
Phase of development: 3 
Objectives:  
 
Primary 
To evaluate the efficacy of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) 5.6 mg in the treatment 
of patients with fibromyalgia. 
 
Secondary 
To evaluate the safety of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) 5.6 mg in the treatment 
of patients with fibromyalgia. 
 
Methodology:  
This is a Phase 3, 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 daily at bedtime for 
the treatment of fibromyalgia.  The study is to be conducted at approximately 35-45 investigational sites 
in the United States. 
 
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.  For extenuating circumstances, 
the duration of the Screening period may be increased to up to 49 days with Medical Monitor approval.  
Note, this trial was ongoing at the time the SARS-CoV-2 virus began to spread in the US, leading to the 
illness known as COVID-19 that is part of the COVID-19 pandemic. 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 (Visit 3, 4, 5), and, only with Medical Monitor approval, Week 14/Visit 6 (or Early 
Termination) for those unable to attend an in-clinic visit due to the COVID-19 pandemic. 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 Early Termination), a home visit should be conducted rather than a telephone 


Protocol No. TNX-CY-F304 
 
CONFIDENTIAL 
Final Amendment Version 1.2 March 27, 2020 Page 5 of 89 
visit in order to collect greater safety data than the telephone visits allow. The Screening phase will be 
followed by the Baseline/Randomization Visit (Visit 2, Day 1), and 4 treatment visits at Weeks 2, 6, 10, 
and 14 (or Early Termination).  The total duration of the study, including Screening, will be 
approximately 15-19 weeks.  The maximum treatment duration will be 14 weeks. 
 
Eligible patients who provide written informed consent will have study assessments performed at 
Screening and will stop all excluded medications during the washout period through the Week 14 visit 
(Visit 6).  Patients will record their average pain intensity for the previous 24 hours in the evening every 
day from Visit 1 through Visit 6 on a diary system.  After recording Baseline Diary scores for at least 7 
days, patients will return to the investigative site for Baseline assessments and randomization (Day 1), 
where they will be randomly assigned to receive TNX-102 SL or matching placebo sublingual tablets in a 
1:1 ratio. 
 
Patients will take the study drug sublingually daily at bedtime, starting on the day that they are 
randomized (Day 1), for 14 weeks.  For the first two weeks of treatment, patients will start on TNX-102 
SL 2.8 mg (1 tablet) or placebo. Upon return to the site1 for the Week 2 visit (Visit 3), all patients will 
have the dose increased to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets.  Patients will 
return to the site1 for assessment of efficacy and safety, as well as dose tolerability, at Weeks 6, 10, and 14 
(or Early Termination). 
 
In scenarios in which TNX-102 SL 5.6 mg, or 2 placebo tablets, is considered intolerable and would 
otherwise lead to study discontinuation, the Investigator may lower the dose back to 1 tablet every night 
(TNX-102 SL 2.8 mg or one placebo tablet).  Re-challenge with 2 tablets TNX-102 SL 2.8 mg (5.6 mg 
dose)/placebo may be attempted at a later date if/when it is deemed clinically warranted by the 
Investigator, or the patient may remain on the lower dose for the remainder of the study.  
 
Patients who wish to withdraw from the study may do so at any time. 
 
Patients will be trained on use of the diary system at the Screening visit.  Each evening, when the patient 
utilizes the diary, the system will prompt the patient regarding daily average pain intensity, sleep quality 
from the previous night, and study drug dosing the previous night (post-randomization). 
 
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 medication-free for at least 21 days prior to randomization.  This will provide 14 days 
off the excluded medication before the patient starts the 7-day run-in phase during which critical baseline 
daily diary efficacy data are collected.  Any additional time required for down-titration would be in 
addition to this 21-day washout requirement.  For this reason, patients can remain in screening for up to 
35 days, which provides an additional 2 weeks for down-titration, if required. 
 
Number of patients (planned):  
Approximately 470 patients 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. 
 
1 All references to a site/study center visit for Weeks 2, 6, 10, and 14 include telephone visits for Weeks 2, 6, and 10, 
and home visits or telephone visit for Week 14/ET that are being allowed due to the circumstances of the COVID-19 
pandemic. 


Protocol No. TNX-CY-F304 
 
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Final Amendment Version 1.2 March 27, 2020 Page 6 of 89 
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 diagnosis of primary FM as defined by the 2016 Revisions to the 2010/2011 
fibromyalgia diagnostic criteria (American College of Rheumatology Preliminary Diagnostic 
Criteria), which includes all of the following: 
a. Generalized pain, defined as pain in at least 4 of 5 regions 
b. Symptoms have been present at a similar level for at least 3 months; and 
c. Widespread pain index (WPI) ≥7 and symptom severity scale (SSS) score ≥5; OR WPI 
between 4-6 and SSS scale score ≥9; and 
d. The patient does not have another disorder that would otherwise explain his/her pain. 
3. The in-clinic 7-day recall NRS average daily pain intensity score at Screening Visit must be ≥ 4 
and ≤ 9. Exceptions are only possible with Medical Monitor approval.  
4. If female, is either not of childbearing potential (defined as postmenopausal for at least 1 year or 
surgically sterile [e.g., bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) or will 
be practicing one of the following methods of birth control throughout the study: 
a. Hormonal methods such as oral, implantable, injectable, or transdermal contraceptives for 
a minimum of one full cycle (based on the patient’s usual menstrual cycle period) before 
study drug administration; 
b. Intrauterine device (IUD); 
c. Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal 
jelly or cream); 
d. Partners of vasectomized males in stable relationships; 
e. Females involved in stable same sex relationships; 
f. Female patients practicing abstinence may have the birth control requirement waived only 
with Medical Monitor approval. 
5. Patients currently receiving non-exclusionary pharmacologic treatment for depression should 
have been clinically stable for at least 3 months prior to randomization, and on stable doses of the 
antidepressant regimen during this 3-month time frame. 
6. 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 formulations of cyclobenzaprine, and benzodiazepines.   
7. The patient is willing and able to comply with all protocol-specified requirements. 
8. The patient is capable of reading and understanding English and has provided written informed 
consent to participate. Separate written, signed informed consent will be required if the patient is 
to participate in the optional pharmacogenomic assessment. A decision not to participate in 
optional pharmacogenomic testing will not affect the patient’s eligibility for the main study. 
9. In addition to satisfying all other eligibility and randomization criteria, the patient has also 
received Medical Monitor Pre-Randomization Approval to proceed to the 
Baseline/Randomization visit.   
 
Exclusion criteria (Assessed at Screening Visit 1): 
 
1. The patient has been diagnosed with infectious or inflammatory arthritis (e.g., rheumatoid 
arthritis, ankylosing spondylitis, psoriatic arthritis), systemic lupus erythematosus, untreated or 
active gout (ie, any acute attacks within past 2 years is exclusionary), or meets criteria for other 
type of systemic autoimmune disease. 


Protocol No. TNX-CY-F304 
 
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Final Amendment Version 1.2 March 27, 2020 Page 7 of 89 
2. The patient has been diagnosed with a complex regional pain syndrome, failed back surgery 
syndrome, persistent or prevalent pain symptoms related to systemic disease (e.g., diabetic 
peripheral neuropathy, post-herpetic neuropathy), untreated hyperparathyroidism, or a history of 
prior surgery, trauma or other source of pain that, in the Investigator’s opinion, would confound 
or interfere with the assessment of the patient’s fibromyalgia pain 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), and Module K (Psychotic 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).  Any 
patient who scores ≥ 7 on the MSI-BPD may be randomized only with Medical Monitor approval. 
5. The patient is at increased risk of suicide on the basis of the Investigator’s judgment, or the results 
of the Beck Depression Inventory-II (BDI-II) (a response > 1 to BDI-II item #9), or the results of 
the Columbia Suicide Severity Rating Scale (C-SSRS) conducted at Screening and Baseline (e.g., 
C-SSRS Type 3, 4 or 5 ideation during the preceding 6 months and any suicidal behavior within 
the past 12 months). 
6. A BDI-II score greater than 24 at either the Screening or Baseline visit.   
7. The patient has participated in any other study with TNX-102 SL. 
8. Based on screening laboratory results, TSH > 1.5 times the upper limit of normal or AST or ALT 
> 2 times the upper limit of normal; 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 (e.g., significant 
arrhythmia; heart block; heart failure; symptomatic coronary artery disease), 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 has a known current clinically significant systemic infection (e.g., HIV, hepatitis). 
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 EC#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 wash-out of the following medications during screening, or 
wash-out is inadvisable: monoamine oxidase inhibitors (30 day washout required), 
levomilnacipran, anticonvulsants (except when used for migraine prophylaxis), amphetamine 
mixed salts, weight loss agents such as phentermine and diethylpropion, muscle relaxants (e.g., 
methocarbamol, baclofen, carisoprodol), stimulants (e.g., methylphenidate, lisdexamfetamine, 
dextroamphetamine), mirtazapine, trazodone, nefazodone, St. John’s wort, any medication known 
to be a strong CYP3A4 inhibitor (Appendix 1), or any of the medications listed in Inclusion 
Criterion #6. 
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. 


Protocol No. TNX-CY-F304 
 
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Final Amendment Version 1.2 March 27, 2020 Page 8 of 89 
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, or interfere with 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 known hypersensitivity to cyclobenzaprine or the excipients in TNX-102 SL or 
placebo formulations. 
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 (e.g., apnea/hypopnea index 5-15), and/or patients whose mild to 
moderate sleep apnea is well-controlled with CPAP or oral device, are allowed at the discretion of 
the Investigator.  Due to the increased risk of sleep apnea, any patient with a BMI >45 must 
receive Medical Monitor approval prior to randomization. 
25. The patient has a history of narcolepsy, cataplexy, periodic involuntary limb movement disorder 
or other documented, clinically significant sleep disorder.  
26. Patient has plans for international travel, or has a work schedule (e.g., requiring night shifts), that 
prevents them from being able to utilize the diary system during its available time window or to 
take study drug on a regular basis. 
27. The patient is currently being treated with sodium oxybate or ketamine or CGRP receptor 
antagonists. 
28. The patient is currently filing or seeking a work disability claim for any reason or condition. 
29. The patient has received an investigational calcitonin gene-related peptide (CGRP) receptor 
antagonist within 90 days of Screening, or any other investigational drug within 30 days of 
Screening.  
 
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 FM pain satisfies the following criteria, as assessed by diary pain scores (24-hour 
recall): 
 2a. A mean pain intensity score ≥4 and ≤9 on the 11-point (0-10) NRS scale for the 7 days  
  
immediately preceding Visit 2, and 
 2b. No more than 2 individual days with a score <4 on the 7 days immediately preceding Visit 
  
2, and 
 2c. No score of 10 on any of the 7 days immediately preceding Visit 2, and  
 2d. Pain scores recorded on at least 5 out of the 7 days immediately preceding Visit 2. 


Protocol No. TNX-CY-F304 
 
CONFIDENTIAL 
Final Amendment Version 1.2 March 27, 2020 Page 9 of 89 
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 starting on Day 1 for 2 
weeks; then patient will take 2 tablets of assigned study drug simultaneously and sublingually starting on 
Day 15 for 12 weeks. If necessary, a drink of water is recommended prior to dosing for patients with a dry 
mouth.  Patients will be asked to keep the 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 dose of 2 tablets (5.6 mg) is considered intolerable and would otherwise lead to 
study discontinuation, the Investigator may lower the dose back to 1 tablet (2.8 mg) per day.  Re-
challenge with 2 tablets (5.6 mg) may be attempted at a later date if/when deemed clinically warranted.   
 
Criteria for Evaluation: 
 
Efficacy: 
 
Primary efficacy endpoint: 
 
 
Change from Baseline to the Week 14 endpoint in the diary NRS weekly average of daily self-
reported average pain severity scores. 
 
Secondary efficacy endpoints:  The 6 secondary efficacy endpoints listed below are considered key 
secondary endpoints and will be tested in that order: 
 
 
Proportion of patients with a Patient’s Global Impression of Change (PGIC) rating of “very 
much improved” or “much improved” at the Week 14 endpoint 
 
Change from baseline in the Fibromyalgia Impact Questionnaire – Revised (FIQR) symptoms 
domain score at the Week 14 endpoint 
 
Change from baseline in the FIQR function domain score at the Week 14 endpoint 
 
Change from baseline in the Patient Reported Outcomes Measurement Information System 
(PROMIS) score for sleep disturbance at the Week 14 endpoint 
 
Change from baseline in the PROMIS score for fatigue at the Week 14 endpoint 
 
Change from baseline in the weekly average of the daily diary assessment of sleep quality at the 
Week 14 endpoint 
 


Protocol No. TNX-CY-F304 
 
CONFIDENTIAL 
Final Amendment Version 1.2 March 27, 2020 Page 10 of 89 
Exploratory efficacy endpoints: 
 
 
Proportion of patients with a ≥30% improvement from baseline to Weeks 1-14 in the daily self-
reported average pain severity score  
 
Proportion of patients with a ≥50% improvement from baseline to Weeks 1-14 in the daily self-
reported average pain severity scores 
 
Proportion of patients with a PGIC rating of “very much improved” or “much improved” at all 
post-randomization clinic visits 
 
Change from baseline in the FIQR total score, overall impact domain score, and individual item 
scores at all post-randomization clinic visits 
 
Change from baseline in the FIQR symptoms domain score and function domain scores at all 
post-randomization clinic visits 
 
Change from baseline in the PROMIS score for sleep disturbance at all post-randomization 
clinic visits 
 
Change from baseline in the PROMIS score for fatigue at all 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 self-reported average pain severity 
scores at Weeks 1-14 
 
Changes from baseline in patient-rated Changes in Sexual Functioning Questionnaire Short-
Form (CSFQ-14) in females and in males, analyzed separately 
 
Safety: 
 
Incidence of adverse events 
 
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 the C-SSRS scale 
 
Changes from baseline in BDI-II scores 
 
Concomitant Medications: 
Patients who are taking certain medications to manage their FM 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 milnacipran, pregabalin, duloxetine, tramadol, tapentadol, gabapentin and other 
anticonvulsants (aside from those used as migraine prophylaxis), any form of cyclobenzaprine (AMRIX®, 
or generic equivalents), amitriptyline and other tricyclic antidepressants, trazodone, narcotics/opioids, 
naltrexone (including CONTRAVE®) and benzodiazepines. 
 
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 for at least 30 days at a 
stable dose (except for allowed antidepressants, which require 90 days at stable dose) prior to the date of 
randomization, and usage is expected to remain stable throughout the study. 
 


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Final Amendment Version 1.2 March 27, 2020 Page 11 of 89 
In addition, certain other medications will also be prohibited and may require washout, or exclusion of the 
patient if washout is not appropriate (e.g., trazodone, mirtazapine, levomilnacipran, nefazodone, 
benzodiazepines, non-benzodiazepine sleep aids, stimulants, sodium oxybate, ketamine, 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 (e.g. 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 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 adverse events.  If there is a requirement 
for acute opioids, corticosteroids, or other treatments that could confound the evaluation of pain at critical 
times (defined as the week prior to Clinic Visits 2, 3, 4, 5 or 6), 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 diary during the week leading up to each clinic visit.      
 
Statistical methods: 
 
Efficacy Analyses: 
The primary efficacy parameter will be the contrast between TNX-102 SL and placebo in the weekly 
mean change from baseline pain score at the endpoint visit.  The weekly pain score will be based on the 
weekly average of the daily diary patient self-reported 24-hour recall average pain severity scores using 
an 11-point (0-10) NRS.   
 
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 
average pain severity 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 for missing 
data.  Covariates in the model will include the fixed categorical effects of treatment, center, 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.  Please see the separate Statistical Analysis Plan (SAP) for more 
details on the primary and secondary analyses.  
 
Safety Analyses: 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will 
be summarized overall and by preferred term and system organ class.  Adverse events will also be 
summarized by severity and relationship to study drug.  Serious AEs, 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, SD, median, minimum, and maximum).  The number of patients with baseline and treatment-
emergent suicidal ideation and/or suicidal behavior or self-injurious behavior, based on the C-SSRS, will 
be summarized by treatment group. 
 








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Final Amendment Version 1.2 March 27, 2020 Page 15 of 89 
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 A brief physical examination will be performed at Baseline and Week 14/ET. For patients where a telephone visit is being conducted for Week 14/ET, the brief 
physical exam will not be required.  
d Clinical laboratory tests (hematology and serum biochemistry) will be performed at Screening and Week 14/ET.  For patients where a telephone visit is being 
conducted for Week 14/ET, the laboratory tests will not be required. TSH will be tested at Screening only. Optional HCV/HBsAg testing may be performed at 
Screening at the discretion of the Investigator or Sponsor. Medical Monitor approval is required prior to testing.   
e 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 where a telephone visit is being conducted, the urine pregnancy test will be performed at home by patient for 
women of child-bearing potential.  
f Vital signs (oral temperature, weight and sitting blood pressure and heart rate [obtained after resting for 5 minutes in a sitting position]) will be measured at 
each visit.  Height will be measured at Screening only. For patients where a telephone visit is being conducted, the vital signs will not be required. 
g A 12-lead electrocardiogram will be obtained at Screening.  All electrocardiograms will be performed and interpreted locally. 
h Clinic staff members will train the patient on how to take the study drug and how to complete the diary.  Patients will be asked to complete their diary every 
evening.  Diary completion will start on the evening of Visit 1 and continue through Week 14.  Diary responses will be monitored during the study. 
i 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 where a telephone visit is being conducted, the study drug will be mailed via courier to their 
home. Patients will be instructed to take one 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. 
j Patients will assess their average daily 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. 
k Any additional (pre-screening) medical findings or medications discovered after the Screening Visit are to be noted in the Medical History, Prior/Concomitant 
Medication Page or Lifetime FM pharmacotherapy page, respectively. 
l PROMIS scales for sleep disturbance and fatigue. 
m The urine drug screen is mandatory at Visit 1.  If the screening 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 V2.  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 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 in which a visual exam is not possible (i.e. 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 


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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. 
*/o The blood draw for the pharmacogenomic assessment can be obtained at any study visit post-Screening (including an Early Termination visit).  Due to 
circumstances caused by the COVID-19 pandemic and 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.  
p Weekly recall of daily average pain intensity on the NRS scale is required at the Screening Visit. Patients should only continue screening if they score ≥4 and 
≤9. A score outside this range will require Medical Monitor approval in order to continue in screening.  
q For telephone visits, the patient will be mailed all the applicable patient reported outcomes for a given visit. The results of the BDI-II will be reviewed with the 
patient (specifically Question #9 which will allow further exploration of any suicidal thoughts or wishes implied by the patient’s self-reported response, if 
applicable) during the phone call. C-SSRS interview should only be conducted after the BDI-II Question #9 inquiry, as any discrepancy between Question #9 
response and C-SSRS suicidal ideation types endorsed for the same assessment period must be resolved to avoid presence of occult suicidal ideation not 
recognized by site staff. 
r Week 2, Week 6, and the 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 (e.g. 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 (e.g. 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.  
 
 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
Table of Contents 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............17 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................22 
5. 
INTRODUCTION ......................................................................................................25 
5.1. 
Overview of Fibromyalgia ..........................................................................................25 
5.2. 
Background of TNX-102 SL ......................................................................................25 
5.3. 
Scientific Rationale .....................................................................................................26 
5.3.1. 
Use of CBP in the Management of FM ......................................................................26 
5.3.2. 
Rationale for Investigating Sublingual Dosing with CBP for Bedtime 
Administration to Treat Fibromyalgia ........................................................................26 
5.3.3. 
Brief Summary of Prior Clinical Experience and Dose Rationale .............................26 
5.4. 
Conclusion for Study Design ......................................................................................28 
6. 
TRIAL OBJECTIVES ................................................................................................29 
6.1. 
Primary Objective .......................................................................................................29 
6.2. 
Secondary Objective ...................................................................................................29 
7. 
INVESTIGATIONAL PLAN .....................................................................................30 
7.1. 
Overall Study Design ..................................................................................................30 
7.2. 
Study Endpoints ..........................................................................................................31 
7.2.1. 
Primary efficacy endpoint ...........................................................................................31 
7.2.2. 
Secondary efficacy endpoints: ....................................................................................32 
7.2.3. 
Exploratory efficacy endpoints: ..................................................................................32 
7.2.4. 
Safety ..........................................................................................................................33 
7.3. 
Number of Patients and Treatment Assignment .........................................................33 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................34 
8.1. 
Informed Consent .......................................................................................................34 
8.2. 
Patient Inclusion Criteria ............................................................................................34 
8.3. 
Patient Exclusion Criteria ...........................................................................................35 


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8.4. 
Randomization Criteria ...............................................................................................37 
8.5. 
Patient Withdrawal Criteria ........................................................................................38 
9. 
TREATMENT OF PATIENTS ..................................................................................39 
9.1. 
Prior and Concomitant Medications ...........................................................................39 
9.2. 
Cannabis/THC Use .....................................................................................................42 
9.3. 
Enrollment of Patients ................................................................................................42 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................43 
10.1. 
Study Drug Packaging, Labeling, and Storage ...........................................................43 
10.2. 
Dosing Instructions .....................................................................................................43 
10.3. 
Dispensing Instructions ..............................................................................................44 
10.4. 
Release of Clinical Study Supplies to the Investigator ...............................................44 
10.5. 
Study Drug Accountability and Reconciliation ..........................................................45 
11. 
STUDY VISITS..........................................................................................................46 
11.1. 
Visit 1 (Day -35 to Day -7) .........................................................................................46 
11.1.1. 
Informed Consent .......................................................................................................46 
11.1.2. 
Screening Overview ....................................................................................................46 
11.1.3. 
Patient Numbering ......................................................................................................47 
11.1.4. 
Screening Assessments and Procedures .....................................................................47 
11.2. 
Visit 2 (Baseline: Day 1) ............................................................................................48 
11.2.1. 
Randomization Criteria ...............................................................................................48 
11.2.2. 
Baseline Visit ..............................................................................................................49 
11.2.3. 
Study Drug Dispensing ...............................................................................................50 
11.2.4. 
Patient Instructions .....................................................................................................50 
11.3. 
Visit 3 (Week 2) ..........................................................................................................50 
11.4. 
Visits 4 and 5 ..............................................................................................................52 
11.5. 
Visit 6 (Week 14 or Early Termination) .....................................................................54 
11.5.1. 
Visit 6 (Week 14) ........................................................................................................54 
11.5.2. 
Early Termination (Post-Randomization) ...................................................................55 
11.6. 
Unscheduled Visit .......................................................................................................57 
12. 
STUDY ASSESSMENTS ..........................................................................................58 
12.1. 
Screening Assessments Not Discussed Elsewhere .....................................................58 
12.1.1. 
Diagnosis of Fibromyalgia (2016 Revisions to the 2010/2011 Fibromyalgia 
Diagnostic Criteria) ....................................................................................................58 


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12.1.2. 
Electrocardiogram .......................................................................................................58 
12.2. 
Efficacy Assessments .................................................................................................58 
12.2.1. 
Daily 24-hour pain recall using 11-point Numerical Rating Scale (NRS) .................58 
12.2.2. 
Patient Global Impression of Change (PGIC) ............................................................59 
12.2.3. 
Fibromyalgia Impact Questionnaire - Revised (FIQR) ..............................................59 
12.2.4. 
Clinic Assessment of Pain (24-hour and weekly recall) .............................................59 
12.2.5. 
PROMIS Scales ..........................................................................................................59 
12.2.6. 
Diary Assessments ......................................................................................................59 
12.2.7. 
Assessment of Changes in Sexual Function: Changes in Sexual Functioning 
Questionnaire Short-Form (CSFQ-14) .......................................................................60 
12.3. 
Safety Assessments .....................................................................................................60 
12.3.1. 
Adverse Events ...........................................................................................................61 
12.3.2. 
Oral Adverse Events ...................................................................................................61 
12.3.3. 
Beck Depression Inventory (BDI-II) ..........................................................................62 
12.3.4. 
Columbia- Suicide Severity Rating Scale (C-SSRS) ..................................................62 
12.3.5. 
Physical Examination and Vital Signs ........................................................................62 
12.3.6. 
Visual Examination of the Oral Cavity ......................................................................63 
12.3.7. 
Clinical Laboratory Assessments ...............................................................................63 
12.3.8. 
Pharmacogenomics Testing ........................................................................................65 
13. 
STATISTICAL CONSIDERATIONS AND ANALYSES ........................................66 
13.1. 
Populations for Analysis .............................................................................................66 
13.2. 
Estimate of Sample Size .............................................................................................66 
13.3. 
Assessment of Demographic and Baseline Characteristics ........................................66 
13.4. 
Efficacy Analyses .......................................................................................................66 
13.4.1. 
Efficacy Endpoints ......................................................................................................66 
13.4.2. 
Primary Efficacy Analysis ..........................................................................................67 
13.4.3. 
Sensitivity Analyses ....................................................................................................68 
13.4.4. 
Secondary Efficacy Analyses .....................................................................................68 
13.4.5. 
Exploratory Efficacy Analyses ...................................................................................68 
13.5. 
Safety Analyses ..........................................................................................................69 
13.6. 
Interim Analyses .........................................................................................................70 
14. 
DEFINITIONS, RECORDING, AND REPORTING OF ADVERSE 
EVENTS .....................................................................................................................71 


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14.1. 
Definition of Adverse Events .....................................................................................71 
14.2. 
Adverse Event Recording ...........................................................................................71 
14.2.1. 
Coding the Adverse Event ..........................................................................................71 
14.2.2. 
Severity of Adverse Event ..........................................................................................71 
14.2.3. 
Relationship of Adverse Events to Study Drug ..........................................................72 
14.3. 
Serious Adverse Events (SAEs) and Serious Adverse Drug Reactions .....................72 
14.4. 
Pregnancy ...................................................................................................................74 
15. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY .................................................................................75 
15.1. 
Protocol Modifications and Deviations ......................................................................75 
15.2. 
Study Termination ......................................................................................................75 
16. 
ETHICAL CONSIDERATIONS................................................................................76 
16.1. 
Ethical Conduct of the Study ......................................................................................76 
16.2. 
Ethics Committee/Institutional Review Board (EC/IRB) Review .............................76 
16.3. 
Written Informed Consent ..........................................................................................76 
17. 
DATA HANDLING, RECORD KEEPING, MONITORING AND AUDITS ..........78 
17.1. 
Maintaining Privacy and Confidentiality....................................................................78 
17.2. 
Maintaining Essential Clinical Documents ................................................................78 
17.3. 
Data Handling .............................................................................................................78 
17.4. 
Case Report Forms (CRFs) .........................................................................................79 
17.5. 
Clinical Laboratory Certification ................................................................................79 
17.6. 
Site Monitoring and Tonix’s Right to Review Records .............................................79 
17.7. 
Audits and Inspections ................................................................................................80 
18. 
CONFIDENTIALITY ................................................................................................81 
18.1. 
Protection of Patient Anonymity ................................................................................81 
18.2. 
Confidentiality of Study Information .........................................................................81 
18.3. 
Publication of Data and Protection of Trade Secrets ..................................................81 
19. 
LIST OF REFERENCES ............................................................................................82 
20. 
APPENDICES ............................................................................................................84 
APPENDIX 1  List of CYP3A4 Inhibitors .................................................................................84 
APPENDIX 2  AMRIX® Package Insert (DATED May 2018) ..................................................85 
 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Study Design and Schedule of Assessments ..............................................................13 
Table 3: 
Clinical Laboratory Assessments ...............................................................................64 
 
 


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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 
BDI-II 
Beck Depression Inventory-II 
BPD 
borderline personality disorder 
BUN 
blood urea nitrogen 
CBD 
cannabidiol 
CBP 
cyclobenzaprine HCl 
CFR 
Code of Federal Regulations 
CGRP 
calcitonin gene-related peptide 
CHW 
Cui, Hung, Wang  
CI 
confidence interval 
CK 
creatine kinase 
COVID-19 
Coronavirus Disease 2019 - viral illness caused by SARS-CoV-2  
CPAP 
continuous positive airway pressure 
CRF 
case report form 
CRO 
contract research organization 
CSFQ-14 
Changes in Sexual Functioning Questionnaire Short-Form 
C-SSRS 
Columbia- Suicide Severity Rating Scale 
CYP3A4 
cytochrome P450 subtype 3A4 
e.g. 
exempli gratia (for example) 
EC 
ethics committee 
ECG 
electrocardiogram 
ER 
extended release 
ET 
early termination, i.e. discontinuation from trial 
EULAR 
European League of Against Rheumatism 
PROs 
Patient-Reported Outcome assessments 
etc. 
et cetera (and other things) 
FDA 
US Food and Drug Administration 
FM 
fibromyalgia 
FIQR 
Fibromyalgia Impact Questionnaire (Revised) 
g 
gram(s) 
GCP 
good clinical practice 
GLP 
good laboratory practice 
H, h 
hour(s) 
HCl 
hydrochloride 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV1 
human immunodeficiency virus type 1 


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HIV2 
human immunodeficiency virus type 2 
i.e. 
id est (that is) 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IR 
immediate release 
IRB 
institutional review board 
IRT 
Interactive Response Technology 
ITT 
intent-to-treat 
IUD 
intrauterine device 
kg 
kilogram(s) 
L 
liter(s) 
LBBB 
left bundle branch block 
LS 
least squares 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
mg 
milligram(s) 
min 
minute(s) 
MINI 
Mini International Neuropsychiatric Interview 
mL 
milliliter(s) 
mmHg 
millimeter(s) of mercury 
MMRM 
mixed-effects model repeated-measures 
msec 
millisecond(s) 
MSI-BPD 
McLean Screening Instrument for BPD 
N, n 
number (of patients) 
NA 
no activity 
NA 
not applicable 
nCBP 
norcyclobenzaprine 
NDA 
New Drug Application 
ng 
nanogram(s) 
nM 
nanomolar(s) 
NRS 
Numeric Rating Scale 
NSAID 
nonsteroidal anti-inflammatory drug 
PGIC 
Patient Global Impression of Change 
pH 
approximate negative logarithm of the hydrogen ion concentration 
PO 
per os (by mouth) 
PRN 
pro re nata (as needed) 
PRO 
patient-reported outcome 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PTSD 
posttraumatic stress disorder 
QTcF 
QT corrected for heart rate using Fridericia’s formula 
RBC 
red blood cell 
SAE 
serious adverse event 


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SAP 
statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 – the virus that 
causes viral illness known as COVID-19 
SD 
standard deviation 
SE 
standard error 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SL 
sublingual 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
SOC 
system organ class 
SOP 
standard operating procedure 
SSS 
symptom severity scale 
SSRI 
selective serotonin reuptake inhibitor 
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 
vs. 
versus 
WBC 
white blood cell 
WHO 
World Health Organization 
WPI 
Widespread Pain Index 
 










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6. 
TRIAL OBJECTIVES 
6.1. 
Primary Objective 
To evaluate the efficacy of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) 5.6 mg in the 
treatment of patients with fibromyalgia. 
6.2. 
Secondary Objective 
To evaluate the safety of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) 5.6 mg in the 
treatment of patients with fibromyalgia. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3, double-blind, randomized, multicenter, 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 
daily at bedtime for the treatment of fibromyalgia.  The study is to be conducted at 
approximately 35-45 investigational sites in the United States. 
The study will consist of a Screening Visit (Visit 1, Days -35 to -8), a Baseline/Randomization 
Visit (Visit 2, Day 1), a Week 2 Visit (where the dose will be increased to 5.6 mg/day), and 3 
more treatment visits (Weeks 6, 10 and 14 or Early Termination).  The period between the 
Screening and Baseline Visit wills be at least 7 days, in order to allow for at least one week of 
daily pain data collection, and up to 35 days, to accommodate any necessary scheduling 
challenges or prohibited medication washout time. For extenuating circumstances, the duration 
of the Screening period may be increased to up to 49 days with Medical Monitor approval, and 
an option for a telephone visit will be available for Weeks 2, 6, and 10 for those unable to attend 
an in-clinic visit due to circumstances related to the COVID-19 pandemic. Additionally, a Week 
14/ET telephone visit or home visit by site staff may be allowed on a case-by-case basis, 
approved by the Medical Monitor, if the only other choice is losing the patient completely from 
the study if patient absolutely cannot come in to the clinic for the visit. The total duration of the 
study, including Screening, will be approximately 15-19 weeks.  The maximum treatment 
duration will be 14 weeks. 
Eligible patients who provide written consent will have study assessments performed at 
Screening and will stop all excluded medications during the washout period, as required, through 
the Week 14 visit (Visit 6). An in-clinic 7-day recall NRS average daily pain intensity score at 
Screening must be ≥ 4 and ≤ 9 in order for the patient to remain eligible. A score outside this 
range will require Medical Monitor approval to remain in screening. 
Patients will be trained on the use of the daily diary at Screening Visit 1.  Patients will be asked 
to record their average daily pain intensity on the 11-point (0-10) NRS scale using 24-hour 
recall, and to provide an assessment of sleep quality from the previous evening, also using an 11-
point NRS scale. Each evening, when the patient completes the diary, the system will prompt the 
patient regarding daily average pain intensity, sleep quality from the previous night, and study 
drug dosing (post-randomization). Due to limitations in the diary completion window, patients 
that 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.   
After completing any required washout of excluded therapies (see next paragraph) 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), where they will be randomly assigned to receive 
TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or matching placebo sublingual tablets in a 1:1 ratio. 
The mean of the 7 days immediately preceding Visit 2 (Baseline Randomization Visit; Day 1) 
will serve as the baseline pre-treatment pain score. 


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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 withdrawal must be accomplished so that the 
patient is medication-free for at least 21 days prior to randomization.  This will provide 14 days 
off the excluded medication before the patient starts the 7-day run-in phase during which critical 
baseline efficacy data are collected by means of the daily diary.  Any additional time required for 
gradual dose reduction/down-titration would be in addition to this 21-day washout requirement.  
For this reason, patients can remain in screening for up to 35 days, which provides an additional 
2 weeks for down-titration, if required. 
Patients will take the study drug sublingually daily at bedtime, starting in the evening of the day 
that they are randomized (Day 1, Visit 2), for 14 weeks.  Patients will be instructed to take one 
tablet (2.8 mg) sublingually daily at bedtime for the first 2 weeks (Days 1-14). Patients will then 
return to the clinic1 at Week 2 (Visit 3) for efficacy and safety assessments, assessment of study 
drug compliance, and the study drug dose will be increased to two tablets (2 x 2.8 mg) taken 
sublingually and simultaneously daily at bedtime. Patients will next return to the clinic1 at Week 
6 (Visit 4) for efficacy and safety assessments, assessment of study drug compliance, and an 
assessment of dose tolerability at the 5.6 mg dose.  If the patient reports intolerable side effects at 
this visit (Visit 4), the Investigator may consider a reduction in dose to one tablet sublingually 
every night, either temporarily or for the remainder of the study, depending on what the 
Investigator considers clinically appropriate. 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 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 
study center1 for safety and efficacy assessments, and assessments of study drug compliance and 
tolerability at Weeks 10 (Visit 5), and 14 (Visit 6) or Early Termination.   
Patients who wish to withdraw from the study may do so at any time.  
The study timeline and events schedule is provided in Table 2. 
7.2. 
Study Endpoints 
7.2.1. 
Primary efficacy endpoint 
 
Change from Baseline to the Week 14 endpoint in the diary NRS weekly average of daily self-
reported average pain severity score. 
 
1 All references to a site/study center visit for Weeks 2, 6, 10, and 14 include telephone visits for Weeks 2, 6, and 10, 
and home visits or telephone visit for Week 14/ET that are being allowed due to the circumstances of the COVID-19 
pandemic. 


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7.2.2. 
Secondary efficacy endpoints:  
The 6 secondary efficacy endpoints listed below are considered key secondary endpoints and 
will be tested in that order. 
• Proportion of patients with a Patient’s Global Impression of Change (PGIC) rating of 
“very much improved” or “much improved” at the Week 14 endpoint  
• Change from baseline in the Fibromyalgia Impact Questionnaire – Revised (FIQR) 
symptoms domain score at the Week 14 endpoint 
• Change from baseline in the FIQR function domain score at the Week 14 endpoint  
• Change from baseline in the Patient Reported Outcomes Measurement Information 
System (PROMIS) score for sleep disturbance at the Week 14 endpoint 
• Change from baseline in the PROMIS score for fatigue at the Week 14 endpoint  
• Change from baseline in the weekly average of the daily diary assessment of sleep 
quality at the Week 14 endpoint 
7.2.3. 
Exploratory efficacy endpoints: 
• Proportion of patients with a ≥30% improvement from baseline to Weeks 1-14 in the 
daily self-reported pain severity score 
• Proportion of patients with a ≥50% improvement from baseline to Weeks 1-14 in the 
daily self-reported pain severity score 
• Proportion of patients with a PGIC rating of “very much improved” or “much 
improved” at all post-randomization clinic visits 
• Change from baseline in the FIQR total score, overall impact domain score, and 
individual item scores at all post-randomization clinic visits 
• Change from baseline in the FIQR symptoms domain score and function domain 
scores at all post-randomization clinic visits 
• Change from baseline in the PROMIS score for sleep disturbance and fatigue at all 
post-randomization clinic visits 
• Change from baseline in the PROMIS score for fatigue at all 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 self-reported average pain 
severity score at Weeks 1-14 
• Changes from baseline in patient-rated Changes in Sexual Functioning Questionnaire 
Short-Form (CSFQ-14) in females and in males, analyzed separately 
Additional exploratory analyses may be defined in the Statistical Analysis Plan (SAP). 


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7.2.4. 
Safety 
• Incidence of adverse events 
• 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 the Columbia- Suicide Severity Rating Scale (C-SSRS) 
scale 
• Changes from baseline in Beck Depression Inventory-II (BDI-II) scores 
7.3. 
Number of Patients and Treatment Assignment 
Approximately 470 patients will be randomized in a 1:1 ratio to treatment with TNX-102 SL 5.6 
mg (2 x 2.8 mg tablets) or SL placebo tablets.  Randomization will be stratified by center.  
Randomized patients who withdraw will not be replaced.  Each patient will participate for 15-19 
weeks in an outpatient clinic setting.  This includes a variable 1 to 5-week screening and washout 
period, and a 14-week treatment period. 


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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 during the screening period: 
1. The patient is male or female 18 to 65 years of age, inclusive. 
2. The patient has a diagnosis of primary FM as defined by the 2016 Revisions to the 
2010/2011 fibromyalgia diagnostic criteria (American College of Rheumatology Preliminary 
Diagnostic Criteria), which includes all of the following: 
a. Generalized pain, defined as pain in at least 4 of 5 regions 
b. Symptoms have been present at a similar level for at least 3 months; and 
c. Widespread pain index (WPI) ≥7 and symptom severity scale (SSS) score ≥5; OR WPI 
between 4-6 and SSS scale score ≥9; and 
d. The patient does not have another disorder that would otherwise explain his/her pain. 
3. The in-clinic 7-day recall NRS average daily pain intensity score at Screening Visit must be 
≥ 4 and ≤ 9. Exceptions are only possible with Medical Monitor approval.  
4. If female, is either not of childbearing potential (defined as postmenopausal for at least 1 year 
or surgically sterile [e.g., bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) 
or will be practicing one of the following methods of birth control throughout the study: 
a. Hormonal methods such as oral, implantable, injectable, or transdermal contraceptives 
for a minimum of one full cycle (based on the patient’s usual menstrual cycle period) 
before study drug administration; 
b. Intrauterine device (IUD); 
c. Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal 
jelly or cream); 
d. Partners of vasectomized males in stable relationships; 
e. Females involved in stable same sex relationships; 
f. Female patients practicing abstinence may have the birth control requirement waived 
only with Medical Monitor approval. 
5. Patients currently receiving non-exclusionary pharmacologic treatment for depression should 
have been clinically stable for at least 3 months prior to randomization, and on stable doses 
of the antidepressant regimen during this 3-month time frame. 
6. 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, 


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amitriptyline and other tricyclic antidepressants, trazodone, narcotics/opioids, naltrexone 
(including CONTRAVE®), all other formulations of cyclobenzaprine, and benzodiazepines.   
7. The patient is willing and able to comply with all protocol-specified requirements. 
8. The patient is capable of reading and understanding English and has provided written 
informed consent to participate. Separate written, signed informed consent will be required if 
the patient is to participate in the optional pharmacogenomic assessment. A decision not to 
participate in optional pharmacogenomic testing will not affect the patient’s eligibility for the 
main study. 
9. In addition to satisfying all other eligibility and randomization criteria, the patient has also 
received Medical Monitor Pre-Randomization Approval to proceed to the 
Baseline/Randomization visit.   
8.3. 
Patient Exclusion Criteria 
Eligible patients who meet any of the following criteria during the screening period should be 
excluded from the study: 
1. The patient has been diagnosed with infectious or inflammatory arthritis (e.g., rheumatoid 
arthritis, ankylosing spondylitis, psoriatic arthritis), systemic lupus erythematosus, untreated 
or active gout, (i.e. any acute attack within past 2 years is exclusionary), or meets criteria for 
other type of systemic autoimmune disease. 
2. The patient has been diagnosed with a complex regional pain syndrome, failed back surgery 
syndrome, persistent or prevalent pain symptoms related to systemic disease (e.g., diabetic 
peripheral neuropathy, post-herpetic neuropathy), untreated hyperparathyroidism, or a history 
of prior surgery, trauma or other source of pain that, in the Investigator’s opinion, would 
confound or interfere with the assessment of the patient’s fibromyalgia pain 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) and Module K (Psychotic 
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). Any patient who scores ≥ 7 on the MSI-BPD may be randomized only with 
Medical Monitor approval. 
5. The patient is at increased risk of suicide on the basis of the Investigator’s judgment, or the 
results of the BDI-II (a response > 1 to BDI-II item #9), or the results of the C-SSRS 
conducted at Screening (e.g., any C-SSRS Type 3, 4 or 5 suicidal ideation during the 
preceding 6 months and any suicidal behavior within the past 12 months) and Baseline (e.g., 
any C-SSRS Type 3, 4, or 5 suicidal ideation or any suicidal behavior since Screening visit). 
6. A BDI-II score greater than 24 at either the Screening or Baseline visit.   
7. The patient has participated in any other study with TNX-102 SL. 


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8. Based on screening laboratory results, thyroid-stimulating hormone (TSH) > 1.5 times the 
upper limit of normal or aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) > 2 times the upper limit of normal; 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 (e.g., significant 
arrhythmia; heart block; heart failure; symptomatic coronary artery disease), 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 has a known current clinically significant systemic infection (e.g., HIV, 
hepatitis). 
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 or locally 
injected 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 EC#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 wash-out of the following medications during screening, 
or wash-out is inadvisable: monoamine oxidase inhibitors (30 days), levomilnacipran, 
anticonvulsants (except when used for migraine prophylaxis), amphetamine mixed salts, 
weight loss agents such as phentermine and diethylpropion, muscle relaxants (e.g., 
methocarbamol, baclofen, carisoprodol), stimulants (e.g., methylphenidate, 
lisdexamfetamine, dextroamphetamine), mirtazapine, trazodone, nefazodone, St. John’s wort, 
any medication known to be a strong CYP3A4 inhibitor (Appendix 1), or any of the 
medications listed in Inclusion Criterion #6. 
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, or interfere with 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. 
 


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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 known hypersensitivity to cyclobenzaprine or the excipients in TNX-102 
SL or placebo formulations. 
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 (e.g., apnea/hypopnea index 5-15), and/or patients whose 
mild to moderate sleep apnea is well-controlled with CPAP or oral device, are allowed at the 
discretion of the Investigator.  Due to the increased risk of sleep apnea, any patient with a 
body mass index (BMI) >45 must receive Medical Monitor approval prior to randomization. 
25. The patient has a history of narcolepsy, cataplexy, periodic involuntary limb movement 
disorder or other documented, clinically significant sleep disorder.  
26. Patient has plans for international travel, or has a work schedule (e.g., requiring night shifts), 
that prevents them from being able to utilize the diary system during its available time 
window or to take study drug on a regular basis. 
27. The patient is currently being treated with sodium oxybate or ketamine or calcitonin gene-
related peptide (CGRP) receptor antagonists. 
28. The patient is currently filing or seeking a work disability claim for any reason or condition. 
29. The patient has received an investigational calcitonin gene-related peptide (CGRP) receptor 
antagonist within 90 days of Screening, or any other investigational drug within 30 days of 
Screening.  
8.4. 
Randomization Criteria 
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 FM pain satisfies the following criteria, as assessed by diary pain scores (24 
hour recall): 
a. A mean pain intensity score ≥4 and ≤9 on the 11-point (0-10) NRS scale for the 7 
days immediately preceding Visit 2, and 


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b. No more than 2 individual days with a 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. Pain scores recorded on at least 5 out of the 7 days immediately preceding Visit 2. 
If the patient does not satisfy these randomization criteria, the patient has failed to qualify for 
this study and should be considered a screen failure, with the reason documented.  With Medical 
Monitor approval, if the patient is otherwise considered a qualified and compliant patient, Visit 2 
may be delayed for up to 7 days to accommodate situations in which the patient has been unable 
to record 5 of 7 days of pain scores due to acceptable extenuating circumstances. There is no 
requirement for a Follow-Up visit for screen failures. 
8.5. 
Patient Withdrawal Criteria 
In accordance with the Declaration of Helsinki, human subjects 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 11.5.2. 


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9. 
TREATMENT OF PATIENTS 
9.1. 
Prior and Concomitant Medications 
Patients who are taking certain medications to manage their FM are eligible for the study if they 
are willing and able (and it is medically reasonable for them) to be withdrawn from those 
medications that are specifically excluded by the protocol and they agree to refrain from further 
usage during this study.  The specific medications that must be withdrawn include milnacipran, 
pregabalin, duloxetine, tramadol, gabapentin, any form of cyclobenzaprine (AMRIX®, 
FEXMID® or generic cyclobenzaprine), tapentadol, amitriptyline and other tricyclic 
antidepressants, trazodone, narcotics/opioids and naltrexone (including CONTRAVE®).  In 
addition, certain other medications are prohibited and may require washout, or exclusion of 
patients for whom washout is not appropriate (e.g., benzodiazepines, anticonvulsants (except 
when used as migraine prophylaxis), levomilnacipran, mirtazapine, nefazodone, St. John’s wort, 
phentermine, diethylproprion, muscle relaxants (e.g., methocarbamol, baclofen, carisoprodol), 
and systemic use of strong CYP3A4 inhibitors as defined in Appendix 1 (i.e., topical use is not 
excluded). 
All patients undergoing washout must complete a 3-week drug-free interval prior to the 
Baseline/Randomization visit (Visit 2); this will provide two weeks of washout prior to the 7 
days leading up to Visit 2 when baseline efficacy data will be collected on the daily diary. Any 
patient with a positive screening UDS who is washing off an opioid, amphetamine, or 
benzodiazepine must return to the clinic for a repeat UDS before they begin their 7-day baseline 
data collection period leading up to Visit 2.   
In general, patients utilizing benzodiazepines on a chronic or regular basis should not be 
considered for the study; however, washout may be considered for those patients utilizing them 
only on an occasional or as-needed basis (e.g, three times per week or less, on average).  In 
addition, patients taking benzodiazepines for restless leg syndrome should not be considered, 
since washout would not be advised. Buspirone, however, is allowed. 
Several benzodiazepines are not easily detected by the in-clinic urine dipstick; therefore, patients 
positive for benzodiazepines at Screening and deemed appropriate for washout will require a 
centrally-interpreted repeat UDS conducted prior to the beginning of the 7-day baseline data 
collection period prior to V2.  All other repeat urine drug screens can be conducted on-site.   All 
repeat UDS results must be confirmed negative before the patient can be randomized.   
Patients using non-benzodiazepine hypnotics (e.g., zolpidem, eszopiclone, zaleplon) on a 
chronic, nightly basis should not be enrolled; however, patients utilizing these medications on an 
infrequent or occasional basis only (e.g., three times per week or less, on average) may be 
considered.  Similar to the benzodiazepines, drugs in this class of medication can negatively 
impact sleep architecture; therefore, patients utilizing either non-benzodiazepines or 
benzodiazepines should be discussed with the Medical Monitor early during the screening 
process to determine their suitability for the study and to determine whether washout is clinically 
advisable.  Patients washing off non-benzodiazepines should not be randomized if they are 
unable to discontinue their use and remain drug-free through their 7-day baseline data collection 
period leading up to Visit 2. The patient’s ability to successfully discontinue their use of 


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excluded sleep therapies should be carefully assessed, since UDS testing is not available for non-
benzodiazepine hypnotics. 
After randomization, sedating antihistamines (e.g., diphenhydramine, hydroxyzine) may be used 
as needed for insomnia; however, patients will need to refrain from their use during the week of 
baseline data collection leading up to Visit 2.  Patients should track their use of sedating 
antihistamines in between study visits so that changes in usage during the course of the study can 
be tracked and recorded.   
The use of melatonin, ramelteon, and valerian root is not restricted.  Similarly, the use of 
cannabidiol (CBD) products is not restricted, but like all other allowed concomitant medications, 
its usage should have been stable for at least 30 days prior to randomization, and usage should 
remain stable during the study.  Additionally, the use of CBD products should not be started after 
randomization.  All CBD products should be added to the concomitant medication source and 
case report form (CRF).  
Due to the exclusion of all opioids 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 with neuropathic pain in addition to fibromyalgia should not be washed off of 
gabapentin, pregabalin or any other anticonvulsant, and therefore should not be considered for 
the study. 
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 withdrawal must be accomplished so that the 
patient is medication free for at least 21 days prior to randomization.  This will provide 14 days 
off the excluded medication before the patient starts the 7-day run-in phase during which critical 
baseline efficacy data are collected by means of the daily diary.  Any additional time required for 
down-titration would be in addition to this 21-day washout requirement.  For this reason, patients 
can remain in screening for up to 35 days, which provides an additional 2 weeks for down-
titration, if required. For extenuating circumstances, the duration of the Screening period may be 
increased to up to 49 days with Medical Monitor approval.   
Other chronic prescription or over-the-counter medication not specifically excluded by an 
exclusion criterion may be continued in the study, provided that the patient has been on this 
medication for at least 30 days at a stable dose (except for allowed antidepressants, which require 
90 days at stable dose) from the date of randomization, and usage is expected to remain stable 
throughout the study.  Allowed medications include, but are not limited to, hormonal therapy 
(contraceptives and replacement therapy), anti-hypertensive agents, lipid-lowering medications, 
selective serotonin reuptake inhibitors (SSRI) and other allowed antidepressants (e.g., 
venlafaxine, desvenlafaxine, bupropion, vilazodone).   
Acetaminophen (up to 3000 mg/day) and non-steroidal anti-inflammatory drugs (NSAIDs) may 
be continued in a stable fashion for osteoarthritis or other allowed indications (e.g., aspirin for 
cardioprophylaxis), or used as needed for other sources of acute, minor pain.  Note that 
acetaminophen and NSAIDs may be taken either on a regular basis, or on an as-needed (prn) 
basis; however, if used as-needed, the Investigator should ascertain the patient’s typical pattern 
of usage (e.g., average dosage and frequency per defined time interval) so that this information 
can be recorded on the CRF.  Any significant change in the patient’s usage of any medication, 


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including those taken only as needed, should result in an update to the CRF.  The CRF entry for 
any prn medication is expected to include an estimation of the patient’s average dosage and 
frequency per defined time interval.   
Patients on allowed antidepressants due to a history of depression should only be considered for 
the study if no changes in antidepressant agent or dose have occurred during the 90 days leading 
up to randomization, and no changes are anticipated or planned during the treatment phase of the 
study.  In addition, FM patients with comorbid depression who are being treated with duloxetine, 
milnacipran, levomilnacipran, monoamine oxidase inhibitors, or tricyclic antidepressants should 
in general not be considered for the study since washout of these agents could destabilize their 
psychiatric status. 
NOTE: Participating patients receiving treatment with antidepressants should be cautioned about 
the possibility of serotonin syndrome, which has been reported in patients receiving 
cyclobenzaprine with SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRI) and related 
agents. This will be included in the ICF. 
New medications that are deemed required, in the opinion of the Principal Investigator or another 
physician, will be allowed, including medications needed to treat adverse events.  After 
randomization, if there is a requirement for treatment with an acute opioid or other treatment that 
may confound the evaluation of pain at critical times during the study (defined as the week prior 
to Visits  3, 4, 5 or 6), 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 these visits.  While it is understood that opioid usage will 
occasionally be necessary and unavoidable, it could have consequences on the patient’s data.  
Similarly, if there is a requirement for acute, short-term opioid usage during the screening phase, 
the start of the 7-day run-in phase should be delayed to ensure at least 2 days between the last 
opioid dose and the beginning of the 7-day run-in phase.  In other words, there may be some 
circumstances when the unexpected requirement for short-term opioid usage, specifically due to 
an acute medical, dental or surgical condition, does not require the full 21-day washout.  This 
provision only applies to acute pain conditions – not to opioid usage due to a flare in patient’s 
FM or other chronic pain condition.  Any requirement for acute opioid usage during the 
screening phase should be brought to the attention of the Medical Monitor to ensure adequate 
washout prior to randomization. 
Patients should refrain from drinking grapefruit juice or eating grapefruit during the study due to 
its ability to inhibit CYP3A4 activity.  Aside from this restriction, there are no other food or fluid 
restrictions in this study except for the instructions pertaining to dosing (Section 10.2). 
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. 
Any concomitant medications or other treatments must be recorded in the patient’s medical 
record and case report form along with the dose and dates of treatment. 
 


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9.2. 
Cannabis/THC Use 
 
Patients utilizing cannabis/THC are to be excluded if MINI 7.0.2 criteria are met for greater than 
MILD Cannabis Use Disorder during the preceding 12 months (prior to the Screening visit), 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. Cannabis/THC 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.  
If study drugs are to be withdrawn for the explicit purpose of participation in this study, the 
patient must have already provided consent and signed an informed consent form before the 
withdrawal or down titration of any drug 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-F304, sponsor name and address, bottle number, quantity, storage conditions, 
usage instructions, and caution statements for investigational new drug, i.e., Caution: New Drug 
– Limited by United States Law to Investigational Use, and Keep Out of Reach of Children and 
Pets.  
Each study drug bottle will contain 40 tablets.  One bottle will be dispensed to each patient at 
Visit 2 (Baseline) and then two bottles will be dispensed at Visit 3 (Week 2), Visit 4 (Week 
6), and Visit 5 (Week 10).  Study drug will be mailed via courier to a patient’s home where a 
telephone visit is scheduled to be conducted. 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 visit1; 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, brief excursions (15-30°C/59-86°F) as defined 
in the Study Reference Manual (Investigational Product Receipt and Storage) are permitted 
without the sponsor’s approval.  
10.2. 
Dosing Instructions 
Patients will be instructed to take 1 tablet of randomly assigned study drug TNX-102 SL 2.8 mg 
or SL 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 one or two SL tablets under their tongue (if two, 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 or drink (or chew gum) for 
at least 15 minutes after dosing, and preferably not to drink any hot, cold or acidic beverage until 
 
1 All references to a site/study center visit for Weeks 2, 6, 10, and 14 include telephone visits for Weeks 2, 6, and 10, 
and home visits or telephone visit for Week 14/ET that are being allowed due to the circumstances of the COVID-19 
pandemic. 




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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), unless a telephone visit, where patients will be asked to count the 
number of tablets remaining in their current bottles, document this on a form provided to patient, 
and return this form and study drug (with bottles) via courier to the site.  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.  For telephone visits, drug accountability by the site 
staff will occur after the study drug is returned to the site via courier. For home visits (Week 14 
or ET only), site staff will collect bottles and conduct accountability upon return to the site. 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 
any patient who is less than 70% compliant with dosing between visits and one of the Medical 
Monitors should be contacted.    
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 (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 informed consent form.  This signed informed 
consent form will be retained in the Investigator’s study file, and the date the patient signed the 
form will be entered into the CRF.  The patient will be provided with a copy of his or her signed 
and dated informed consent form.  The patient will be required to sign all updated informed 
consents. 
11.1.2. 
Screening Overview 
The first study visit, Screening Visit 1, will be where the study is explained to the prospective 
study patient, where written informed consent will be obtained and documented, and where 
certain protocol-specified study procedures and assessments will be completed.  Screening Visit 
1 will start a variable length screening period.  The length of the screening 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 wash-out 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 wash-out, 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 (e.g. 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 wash-out 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 (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 
• Inclusion/exclusion criteria 
• Demographics 
• Medical history 
• Confirmation that patient satisfies the 2016 Revisions to the 2010/2011 fibromyalgia 
diagnostic criteria (2010 American College of Rheumatology provisional diagnostic 
criteria/2011 self-report modification for survey and clinical research) 
• Prior medication history 
• Lifetime fibromyalgia pharmacotherapy history 
• NRS assessment of 7-day recall of average daily pain. Patients should only continue 
screening if they score ≥4 and ≤9. A score outside this range will require Medical 
Monitor approval in order to continue. 
• 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), and K (Psychotic Disorders) 
• MSI-BPD 
• BDI-II.  Any patient with a BDI-II total score > 24 or a response of 2 or 3 to item #9 
(suicidal ideation) is not eligible for randomization. 
• “Baseline/Screening” version of the C-SSRS.  Any patient with C-SSRS Type 4 or 5 
ideation during the preceding 6 months or any suicidal behavior during the preceding 
12 months should be screen failed. 
a. Results of the C-SSRS and BDI-II should be reviewed together at each visit to 
ensure (1) the patient is not experiencing suicidal ideation or worsening 
depression that requires intervention and (2) both scales are providing a consistent 
clinical picture of the patient with regard to suicidality. 
• Physical examination, including vital signs, height, weight and BMI. Patients with 
BMI>45 must receive Medical Monitor approval prior to randomization. 
• 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 


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floor of the mouth. Any abnormalities should be noted on the oral cavity examination 
source document. 
• Clinical laboratory tests 
• Drug screening 
• Serum pregnancy test (for women of child-bearing potential) 
• 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 instructed regarding the questions that will be asked of them on the daily diary 
and 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 that are planning on 
international travel during the study period, or who work night shifts, should not 
be considered for the study. 
b. Receive an appointment to return to the clinic for Visit 2. 
c. Receive a schedule for down-titration (if required) of any prohibited medications 
to be discontinued. 
11.2. 
Visit 2 (Baseline: Day 1) 
Visit 2 should be scheduled after the patient has completed their medication wash-out 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, will undergo several baseline assessments at 
this visit, and 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 are eligible for randomization: 
1. Continues to meet all inclusion and exclusion criteria, including urine and blood test results, 
and is familiar with the diary system. 
2. Patient’s FM pain satisfies the following criteria, as assessed by diary pain scores (24-hour 
recall): 
a. A mean 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 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 


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d. 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: 
• Confirm patient’s eligibility based on the diary data collected during the preceding 7 
days   
• Review completed diary data with the patient 
• Update medical history (with any changes noted since screening) 
• Assess changes in medication history and concomitant medications 
• Have the patient complete the BDI-II.  If the BDI score is >24, the patient is not 
eligible for randomization and should be screen failed.  In addition, a score > 1 on 
item #9 (suicidal ideation) is exclusionary. 
• 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. 
a. Results of the C-SSRS and BDI-II should be reviewed together to ensure (1) the 
patient is not experiencing suicidal ideation or worsening depression that requires 
intervention and (2) both scales are providing a consistent clinical picture of the 
patient with regard to suicidality. 
• Assess occurrence of adverse events 
• Conduct a brief physical examination, including vital signs and weight 
• Conduct a visual examination of the oral cavity.  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. 
• Perform urine pregnancy test (for women of child-bearing potential) 
• Patient should complete the following patient-reported outcomes (PRO): 
a. FIQR 
b. Clinic administered assessment of pain by both 24-hour and weekly recall using 
11-point (0-10) NRS scale 
c. PROMIS scales for sleep disturbance and fatigue 
d. CSFQ-14 female or male version, as appropriate 
• Ensure that all PROs were accurately and fully completed 


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• Once it has been confirmed that the patient remains eligible, randomize patient via 
IRT Randomization System 
• Dispense bottle of double-blind study drug as assigned via the IRT 
• Review patient instructions regarding study drug dosing and diary completion 
(Section 10.2 and Section 12.2.6). 
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 (e.g., bitter, metallic, unpleasant) after dosing do not 
require unscheduled examinations.   
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 (i.e. extenuating circumstances due to COVID-19 pandemic), a telephone 
visit is an option. All assessments should be performed with exceptions of the ones specifically 
noted with comments in parenthesis.  
The following assessments and procedures are scheduled for this visit in the following general 
order: 
• Review completed diary data and diary compliance with the patient 
• Assess changes in medication history and concomitant medications 


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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). 
• Have the patient complete the BDI-II  
• Administer the “Since Last Visit” version of the C-SSRS 
a. Results of the C-SSRS and BDI-II should be reviewed together to ensure (1) the 
patient is not experiencing suicidal ideation or worsening depression that requires 
intervention and (2) both scales are providing a consistent clinical picture of the 
patient with regard to suicidality. (Telephone visit exception – response to 
Question #9 of the BDI-II is reviewed with the patient and C-SSRS is 
administered over the phone). 
• Assess occurrence of adverse events 
• 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. PGIC 
b. FIQR 
c. Clinic administered assessment of pain by both 24-hour and weekly recall using 
11-point (0-10) NRS scale 
d. PROMIS scales for sleep disturbance and fatigue 
• Ensure that all PROs were accurately and fully completed 
• Vital signs (Telephone visit exception – vital signs are not required) 
• 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, 
PI and Medical Monitor should also confer on whether study drug should be 
discontinued.)  


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• Discuss the scheduled increase in dose of study drug from one sublingual tablet (Days 
1-14) to two 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 
(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 and confirm that the increase 
in drug dosing to two tablets sublingually at bedtime is understood by patient 
• Perform in-clinic urine pregnancy test (for women of child-bearing potential). 
(Telephone visit exception – urine pregnancy test will be performed at home by 
patient for women of child-bearing potential).  
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. If this is a telephone visit, the patients will be 
instructed to return the PROs and study drug (and bottle) to the site via courier.   
11.4. 
Visits 4 and 5 
Visits 4 and 5 are similar study visits that are scheduled to be conducted after 6, and 10 weeks of 
treatment, respectively.  Visit 4 should occur on Day 43 ±7 days and Visit 5 should occur on Day 
71 ± 7 days. For those patients unable to return to the site (i.e. extenuating circumstances due to 
COVID-19 pandemic), a telephone visit is an option for both Visit 4 and Visit 5. All assessments 
should be performed with exceptions of the ones specifically noted with comments in 
parenthesis.  
The following assessments and procedures are scheduled for these visits in the following general 
order: 
• Review completed diary data and diary compliance with the patient 
• Assess changes in medication history and concomitant medications 
• Assess study drug compliance and collect previously dispensed study drug and bottles 
(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).  
• Have the patient complete the BDI-II  
• Administer the “Since Last Visit” version of the C-SSRS 
a. Results of the C-SSRS and BDI-II should be reviewed together to ensure (1) the 
patient is not experiencing suicidal ideation or worsening depression that requires 


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intervention and (2) both scales are providing a consistent clinical picture of the 
patient with regard to suicidality. (Telephone visit exception – response to 
Question #9 of the BDI-II is reviewed with the patient and C-SSRS is 
administered over the phone).  
• Assess occurrence of adverse events 
• 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. PGIC 
b. FIQR 
c. Clinic administered assessment of pain by both 24-hour and weekly recall using 
11-point (0-10) NRS scale 
d. PROMIS scales for sleep disturbance and fatigue 
• Ensure that all PROs were accurately and fully completed  
• Vital signs (Telephone visit exception – vital signs are not required) 
• 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, 
PI and Medical Monitor should also confer on whether study drug should be 
discontinued.) 
• Dispense new bottles (unopened) of double-blind study drug as assigned by IRT 
(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 and drug dosing 
• Perform in-clinic urine pregnancy test (for women of child-bearing potential) 
(Telephone visit exception – urine pregnancy test will be performed at home by 
patient for women of child-bearing potential).  
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 study drug back to the 


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clinic at their next visit. If this is a telephone visit, the patients will be instructed to return the 
PROs and study drug (and bottles) to the site via courier.   
11.5. 
Visit 6 (Week 14 or Early Termination) 
11.5.1. 
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. 
• Assess changes in medication history and concomitant medications 
• Assess study drug compliance and collect previously dispensed study drug and bottles 
(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).  
• Have patient complete the BDI-II  
• Administer the “Since Last Visit” version of the C-SSRS 
a. Results of the C-SSRS and BDI-II should be reviewed together at each visit to 
ensure (1) the patient is not experiencing suicidal ideation or worsening 
depression that requires intervention and (2) both scales are providing a consistent 
clinical picture of the patient with regard to suicidality. (Telephone visit exception 
– response to Question #9 of the BDI-II is reviewed with the patient and C-SSRS 
is administered over the phone). 
• Assess occurrence of adverse events 
• Have 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): 


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a. PGIC 
b. FIQR 
c. Clinic administered assessment of pain by both 24-hour and weekly recall using 
11-point (0-10) NRS scale 
d. PROMIS scales for sleep disturbance and fatigue 
e. CSFQ-14 female or male version, as appropriate 
• Ensure that all PROs were accurately and fully completed  
• Brief physical examination, including vital signs, weight (Telephone visit exception – 
brief physical exam, vital signs, and weight are not required) 
• 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.) 
• Obtain blood for clinical laboratory tests (Telephone visit exception – laboratory tests 
are not required). 
• Perform in-clinic urine pregnancy test (for women of child-bearing potential) 
(Telephone visit exception – urine pregnancy test will be performed at home by 
patient for women of child-bearing potential). 
11.5.2. 
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 
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 


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Patients who wish to terminate their participation in the study should be instructed to come to the 
clinic for an Early Termination Visit.  The purpose of the Early Termination visit is to obtain 
critical information about the patient’s participation and should be scheduled preferably before 
there has been a substantial lapse in study 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 
• Assess changes in medication history and concomitant medications 
• Assess study drug compliance (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).  
• Have patient complete the BDI-II  
• Administer the “Since Last Visit” version of the C-SSRS 
a. Results of the C-SSRS and BDI-II should be reviewed together to ensure (1) the 
patient is not experiencing suicidal ideation or worsening depression that requires 
intervention and (2) both scales are providing a consistent clinical picture of the 
patient with regard to suicidality. (Telephone visit exception – response to 
Question #9 of the BDI-II is reviewed with the patient and C-SSRS is 
administered over the phone). 
• Assess occurrence of adverse events 
• 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. PGIC 
b. FIQR 
c. Clinic administered assessment of pain by both 24-hour and weekly recall using 
11-point (0-10) NRS scale 
d. PROMIS scales for sleep disturbance and fatigue  
e. CSFQ-14 female or male version, as appropriate 
• Brief physical examination, including vital signs, weight (Telephone visit exception – 
brief physical exam, vital signs, and weight are not required) 
• Inspection 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 


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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.) 
• Obtain blood for clinical laboratory tests (Telephone visit exception – laboratory tests 
are not required). 
• Perform in-clinic urine pregnancy test (for women of child-bearing potential) 
(Telephone visit exception – urine pregnancy test will be performed at home by 
patient for women of child-bearing potential). 
Once these assessments have been completed, the patient may be discharged from the study, 
provided that there is no need for additional follow-up to continue to monitor an adverse event or 
other condition. 
11.6. 
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.   


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12. 
STUDY ASSESSMENTS 
12.1. 
Screening Assessments Not Discussed Elsewhere 
12.1.1. 
Diagnosis of Fibromyalgia (2016 Revisions to the 2010/2011 Fibromyalgia 
Diagnostic Criteria) 
The patient is eligible for this study if he/she has a diagnosis of primary FM as defined by the 
2016 Revisions to the 2010/2011 Fibromyalgia Diagnostic Criteria (2010 American College of 
Rheumatology provisional diagnostic criteria/2011 self-report modification for survey and 
clinical research) (Wolfe et al, 2016) (Inclusion Criterion # 2).  This diagnosis is determined by 
satisfaction of all of the following: 
• Generalized pain, defined as pain in at least 4 of 5 regions, and  
• Symptoms have been present at a similar level for at least 3 months; and  
• WPI score ≥7 and SSS score ≥5; OR WPI between 4-6 and SSS score ≥9 
• The patient does not have another disorder that would otherwise explain his/her pain. 
The 2016 Fibromyalgia Diagnostic Criteria will be assessed at Visit 1.   
12.1.2. 
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 (e.g., significant arrhythmias or heart block, left bundle 
branch block (LBBB), 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. 
12.2. 
Efficacy Assessments 
The primary efficacy endpoint and many of the secondary and exploratory efficacy endpoints in 
this study are derived from subjective 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. 
12.2.1. 
Daily 24-hour pain recall using 11-point Numerical Rating Scale (NRS) 
Patients will provide a numeric assessment of their pain (24-hour recall), via the diary, using an 
11-point (0=no pain to 10=worst possible pain) NRS scale.  Patients will be asked to complete 
this assessment on a daily basis during the pre-treatment run-in period and throughout the 


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double-blind treatment period.  Additional information regarding the patient diary is provided in 
Section 12.2.6. 
12.2.2. 
Patient Global Impression of Change (PGIC) 
The PGIC is a FM-specific validated instrument to gauge the patient’s assessment of change in 
condition.  This form will be completed by the patient at Visits 3, 4, 5 and 6.  The patient will 
answer a single question:  
Since the start of the study, overall my fibromyalgia is: 
1 = Very much improved 
2 = Much improved 
3 = Minimally improved 
4 = No change 
5 = Minimally worse 
6 = Much worse 
7 = Very much worse 
 
12.2.3. 
Fibromyalgia Impact Questionnaire - Revised (FIQR) 
The patient’s total score on the Fibromyalgia Impact Questionnaire (revised version) will be 
assessed at Visits 2, 3, 4, 5 and 6.  The FIQR is made up of 3 domains: functional (9 questions), 
overall impact (2 questions) and symptoms (10 questions). 
12.2.4. 
Clinic Assessment of Pain (24-hour and weekly recall) 
In addition to the diary assessments of 24-hour pain recall (Section 12.2.1), patients will be asked 
to rate their average pain on paper using the 11-point (0-10) NRS scale at Visits 2, 3, 4, 5 and 6 
using both a 24-hour and 7-day recall interval.  There is no requirement to reconcile the pain 
responses obtained from these paper assessments to the 24-hour daily diary assessments. 
12.2.5. 
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. 
Two PROMIS Scales will be assessed in this study, including the sleep disturbance scale 
(version 8a) and the fatigue scale (version 8a).  Each of these two scales will be assessed at 
Visits 2, 3, 4, 5 and 6. 
12.2.6. 
Diary Assessments 
The daily diary 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 need to receive instructions and a password that uniquely 
identifies them when they log into the system along with instructions about what to do if they 
have difficulty completing the diary. 
 


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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 average pain during the past 24 hours on a scale from 0-10, where zero is 
no pain and 10 is worst possible pain. 
• 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) 
 
The study staff will be expected to monitor patient adherence in completing the diary throughout 
the study, and will be instructed to call the patient should any problems or significant non-
adherence 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 who have been 
randomized should be encouraged to continue to complete their diary.  Patients will receive a 
reminder to complete their diary if they miss diary entries.  Patients who miss two 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. 
12.2.7. 
Assessment of Changes in Sexual Function: Changes in Sexual Functioning 
Questionnaire Short-Form (CSFQ-14) 
The CSFQ-14 (Keller et al. 2006) is validated scale with internal reliability designed to allow a 
patient to self-evaluate his or her sexual behaviors or problems in a number of areas.  The CSFQ-
14 will be administered at Baseline (Visit 2) and Week 14/ET (Visit 6).  It yields a total score, 
three subscales corresponding to phases of the sexual response cycle (i.e. desire, arousal, 
orgasm), and five subscales corresponding to important dimensions of sexual functioning.  It is 
considered a useful scale for assessing sexual side effects of medications.  For all items, higher 
scores reflect higher sexual functioning.  For 12 of the 14 items, higher sexual functioning 
corresponds to greater frequency or enjoyment/pleasure (e.g. 1=never to 5 = every day).  For two 
items (item 10, assessing loss of interest after arousal for women and priapism for men, and item 
14, assessing painful orgasm), higher sexual functioning corresponds to lower frequency (e.g. 
1=every day; 5=never). Items 10 and 14 are included in the total score but not in any subscale 
scores. 
12.3. 
Safety Assessments 
Safety will be assessed by evaluation of adverse events, vital signs, responses on the Columbia-
Suicide Severity Rating Scale, responses on the BDI-II, and by clinical laboratory and physical 
examination findings, including visual inspection of the oral cavity. 
 


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12.3.1. 
Adverse Events 
Patients will be monitored for AEs throughout the study.  Any clinically significant abnormal 
findings at screening should be recorded in medical history.  Adverse Events 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.   
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 fibromyalgia 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 adverse events. 
Additional information regarding definition and reporting requirements for adverse events, 
serious adverse events, and pregnancies is provided in Section 14. 
12.3.2. 
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 adverse event, 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. 


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12.3.3. 
Beck Depression Inventory (BDI-II) 
The BDI-II is a 21-item measure of the severity of current depressive symptoms, extensively 
validated for use in both medical and mental health populations.  While this instrument does not 
provide a psychiatric diagnosis of depression, it does provide a continuous scale for measuring 
the severity of depressive symptomatology.  Scoring allows for the identification of mild, 
moderate, and severe levels of depressive symptoms, and for the quantification of change in 
status over time. 
The patient will be asked to complete this questionnaire at all in-clinic study visits, and for all 
telephone visits.  The BDI-II will be sent by courier to the patient in advance of the phone call. 
At Visit 1 and Visit 2, patients whose responses are indicative of suicidal ideation, as defined by 
a response to Item #9 of >1, will be excluded from participation, and appropriate intervention 
prescribed.  In addition, patients whose total BDI score is > 24 at either Visit 1 or Visit 2 will not 
be eligible for randomization and should be screen failed (and referred for appropriate 
psychological evaluation or care, if indicated).  After Visit 1, the responses to Question #9 
should be monitored to ensure that there is no increase in suicidal ideation during the study (and 
to assess correlation with C-SSRS findings) and the total score also followed to ensure the 
patient’s psychological status remains stable. 
12.3.4. 
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 Columbia-Suicide 
Severity Rating Scale are suggested probes.  Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
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 
behavior. Patients whose responses are indicative of suicidal ideation with intent and/or plan 
(e.g., 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”.  
Note that if there has been a significant change in responses indicative of increased suicide risk, 
appropriate intervention should be prescribed. 
12.3.5. 
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, oral temperature, and weight) will be assessed 
at Visits 1, 2, 3, 4, 5 and 6 (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 


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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). 
12.3.6. 
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. 
 
12.3.7. 
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 Screening Visit 1 and at Visit 6 (Week 14) or Early Termination, aside from urine pregnancy 
tests and ad hoc urine drug screens.  
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.   
A centrally analyzed urine drug screen (UDS) will be performed at Visit 1.  If the patient has a 
positive drug screen at Visit 1 due to a drug of abuse (e.g., 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 


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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 (e.g., 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, or 
ALT or AST level > 2 times the upper limit of normal, is exclusionary; however, the patient may 
remain in screening to undergo repeat LFT assessments if a transient abnormality (eg, viral illness; 
effects of a medication being discontinued, etc) is thought to be responsible for their initial 
elevation.   
 
Table 3: 
Clinical Laboratory Assessments 
 
Clinical chemistry 
Hematology 
Alanine aminotransferase (ALT/SGPT) a 
Hematocrit 
Alkaline phosphatase 
Hemoglobin 
Aspartate aminotransferase (AST/SGOT) a 
MCH concentration (MCHC) 
Bicarbonate 
Mean corpuscular hemoglobin (MCH) 
Bilirubin (direct and total) 
Mean corpuscular volume (MCV) 
Blood urea nitrogen (BUN) 
Platelet count 
Calcium 
Red blood cell (RBC) count 
Chloride 
WBC differential 
Cholesterol (total) 
Neutrophil count (absolute and %) 
Creatine kinase (CK) 
Lymphocyte count (absolute and %) 
Creatinine 
Monocyte count (absolute and %) 
Glucose 
Eosinophil count (absolute and %) 
LDH 
Basophil count (absolute and %) 
Phosphorus 
White blood cell (WBC) count 
Potassium 
Red blood cell distribution width (RDW) 
Protein (albumin and total) 
 
Sodium 
 
HbA1c only if glucose > 180 mg/dL 
 
Thyroid-stimulating hormone (TSH) c at 
screening 
Serum Pregnancy Test at Screeningb 
Free T4 only if TSH is outside of normal limits 
Urine Pregnancy Test (qualitative dipstick)b 
Pharmacogenomic testing (optional; can be 
obtained at any visit post-Screening, including 
an Early Termination visit) 
Urine Drug Screend 
a  Level greater than 2 times the upper limit of normal is an exclusion (if persistent upon repeat). 


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b Pregnancy testing for females of child-bearing potential only.  A positive pregnancy test is exclusionary (Visit 1 or Visit 2) or 
mandates withdrawal from the study (all other visits). 
c TSH level greater than 1.5 times higher than the upper limit of normal is exclusionary at Visit 1. 
d Urine drug screening will be conducted on all patients at Screening and, if necessary, 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.  
12.3.8. 
Pharmacogenomics Testing 
For pharmacogenomic analysis, a single blood draw collected in one PAXgene DNA tube will be 
obtained from each patient after they have provided separate written, signed informed consent 
for pharmacogenomic analysis. Due to circumstances caused by the COVID-19 pandemic and 
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). The purpose 
of this testing is to allow exome sequencing and analysis for genetic variants related to treatment 
response to TNX-102 SL. It is presumed that unused extracted DNA sample will be stored up to 
fifteen years, and potentially utilized to develop a pharmacogenomic test for determining 
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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Secondary Efficacy Endpoints:  
 
The six secondary efficacy endpoints listed below are considered key secondary endpoints 
and will be tested in that order: 
• Proportion of patients with a PGIC rating of “very much improved” or “much 
improved” at the Week 14 endpoint  
• Change from baseline in the FIQR symptoms domain score at the Week 14 endpoint 
• Change from baseline in the FIQR function domain score at the Week 14 endpoint 
• Change from baseline in the PROMIS score for sleep disturbance at the Week 14 
endpoint 
• Change from baseline in the PROMIS score for fatigue at the Week 14 endpoint 
• Change from baseline in the weekly average of the daily diary assessment of sleep 
quality at the Week 14 endpoint 
 
 
Exploratory efficacy endpoints: 
• Proportion of patients with a ≥30% improvement from baseline to Weeks 1-14 in the 
daily self-reported average pain severity score  
• Proportion of patients with a ≥50% improvement from baseline to Weeks 1-14 in the 
daily self-reported average pain severity scores 
• Proportion of patients with a PGIC rating of “very much improved” or “much 
improved” at all post-randomization clinic visits 
• Change from baseline in the FIQR total score, overall impact domain score, and 
individual item scores at all post-randomization clinic visits 
• Change from baseline in the FIQR symptoms domain score and function domain 
scores at all post-randomization clinic visits 
• Change from baseline in the PROMIS score for sleep disturbance at all post-
randomization clinic visits 
• Change from baseline in the PROMIS score for fatigue at all 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 self-reported average pain 
severity scores at Weeks 1-14 
• Changes from baseline in patient-rated Changes in Sexual Functioning Questionnaire 
Short-Form (CSFQ-14) in females and in males, analyzed separately 
13.4.2. 
Primary Efficacy Analysis 
The primary efficacy parameter will be the contrast between active and placebo in the weekly 
mean change from baseline pain score at the Week 14 endpoint.   The weekly pain score will be 


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based on the weekly average of the daily patient self-reported 24-hour recall average pain 
severity scores using an 11-point (0-10) NRS.   
The primary ITT analysis will provide an estimate of 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 average pain severity 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 MMRM approach with multiple imputation for missing data.  
Covariates in the model will include the fixed categorical effects of treatment, center, 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.  Please see the separate SAP for 
more details on the primary and secondary analyses. 
13.4.3. 
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. 
13.4.4. 
Secondary Efficacy Analyses 
Secondary efficacy analyses will be based on the ITT population only.  For PGIC, patients with a 
“very much improved” or “much improved” response at the Week 14 endpoint will be 
considered responders. Patients with results in any other category or who discontinue early will 
be considered non-responders.  PGIC responder status (yes/no) will be analysed using logistic 
regression with treatment and site as categorical effects.  In addition, odds ratios and 
corresponding 95% confidence intervals will be presented. 
Analysis of continuous secondary endpoints and adjustments for missing data will be described 
in detail in the SAP.  Significance tests of treatment differences will be tested at the two-sided 
0.05 level and corresponding 95% confidence intervals will be calculated. 
To adjust for multiplicity and to control for overall type I error, a sequential test procedure will 
be applied to the efficacy endpoints.  If the primary analysis produces a result that is statistically 
significant at the 0.05 level, a significance level of 0.05 will be used for comparing the secondary 
endpoints in an ordered fashion.  If the analysis for a secondary endpoint does not produce a 
statistically significant result at the 0.05 level, then the remaining secondary endpoint analyses 
will automatically be considered non-significant regardless of the p-value produced. The order in 
which the secondary endpoints are to be tested will be specified in the SAP. 
No other adjustments for multiplicity will be made and other p-values displayed in the output 
will be considered for descriptive summary purposes only and will not be used for formal 
inference.  Full details regarding the statistical analyses for the listed endpoints, including 
graphical presentations, can be found in the SAP. 
13.4.5. 
Exploratory Efficacy Analyses 
Exploratory efficacy analyses will be based on the ITT population.  Details on exploratory 
efficacy analyses can be found in the SAP. 


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13.5. 
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 Adverse Events 
• 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 
• Changes from baseline in BDI-II scores 
All AEs, treatment-emergent adverse events (TEAE), and serious adverse events (SAE) 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 on-treatment assessment for each 
clinical laboratory analyte and each treatment group.  95% confidence intervals will be presented 
for change from baseline. 


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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 (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline at each assessment time point and last on-treatment assessment will be 
calculated for vital signs including weight, BMI, body temperature, pulse rate, systolic blood 
pressure and diastolic blood pressure. 95% confidence intervals will be presented for change 
from baseline. 
Based on the C-SSRS results, the overall number of patients with lifetime and/or current suicidal 
ideation (by item and category), suicidal behavior (by item and category), or self-injurious 
behavior at the screening and baseline visit will be summarized by visit and treatment group.  
Additionally, the overall number of patients with any suicidal ideation or behavior (by type and 
in total) or self-injurious behavior while on-treatment will be provided by treatment group. 
Patients will only be counted once for on-treatment at the worst-case response for each item. 
Physical examination data and oral examination data will be presented in data listings. 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline at each assessment time point and last on-treatment assessment will be 
calculated for BDI-II scores. 95% confidence intervals will be presented for change from 
baseline. 
13.6. 
Interim Analyses 
An interim analysis will be performed once 50% of the planned patients have enrolled and those 
patients have either completed or discontinued the study.  The purpose of the interim will be to 
potentially increase the sample size to maintain statistical power conditioned on the results of the 
first 50% of patients; or continue as planned if conditional probability of success at Week 14 is 
above a pre-specified threshold; or to stop the study early for success or for futility if the 
conditional power is sufficiently low.  The study team will only be informed of the 
recommendation to maintain the original sample size, increase the sample size (by a fixed, pre-
specified amount) or discontinue the study for success or for failure (at which point unblinding 
would occur).    
For the primary and key secondary outcomes, the results from before and after the interim will 
be combined with Cui, Hung, Wang (CHW) methodology (Cui et al, 1999).  Full details of the 
interim analysis will be included in the SAP and 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 Conference on Harmonization (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 subject 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® will be used as the 
standard coding dictionary for AEs and in describing the patient’s medical history, and the 
World Health Organization (WHO) Drug Dictionary will be used to code concomitant 
medications.  Informal descriptions should be avoided. 
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. 
A serious adverse event (experience) or reaction is any untoward medical occurrence that, at any 
dose:  
• Results in death, 
• Is life-threatening, 
• Requires in-patient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, 
• Is a congenital anomaly/birth defect, or 
• Is an important medical event 
 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event.  It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
 




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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.   
14.4. 
Pregnancy 
The active pharmaceutical product in TNX-102 SL is cyclobenzaprine HCl, which is in 
Pregnancy Category B (See Appendix 2 for AMRIX® Package Insert).  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 (i.e., birth or voluntary or spontaneous 
termination of the pregnancy).  Any patient found to be pregnant at any time during the study 
will be withdrawn from the study immediately.  Any pregnancy outcome that meets the criteria 
for an SAE will be reported as an SAE. 


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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 enter patients at an acceptable rate 
• Insufficient adherence to the requirements of the protocol 
• Insufficient provision of complete and evaluable data 
• Plans to modify, suspend, or discontinue development of the study drug 
In the event that the study is terminated prematurely, all study materials must be returned to 
Tonix or its designee. 
 


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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), any EC requirements 
relative to clinical studies. As required by the US FDA, the study drug may not be shipped to any 
participating Investigator until the requisite study documentation has been submitted to the IND. 
Should a conflict arise, the Investigator will follow whichever law or guideline affords the 
greater protection to the individual patient.  The Investigator will also make sure he or she is 
thoroughly familiar with the appropriate administration and potential risks of administration of 
the study drug, as described in this protocol and the Investigator’s Brochure, prior to the 
initiation of the study. 
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 informed consent forms, and the informed consent procedures must be submitted to 
the EC/IRB for review and approved before the enrollment of any patient into the trial. 
All types of patient recruitment or advertising information must be submitted to Tonix or its 
designee and to the EC/IRB for review and approval prior to implementation.  EC/IRB approval 
of any protocol amendments must be received before any of the changes outlined in the 
amendments are put into effect, except when the amendment has been enacted to eliminate a 
potential hazard to study patients.  In such cases, the chair of the EC/IRB should be notified 
immediately and the amendment forwarded to the EC/IRB for review and approval. 
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 
Subjects,” the Health Insurance Portability and Accountability Act (HIPAA) regulations, and all 
other applicable regulatory requirements.  A properly executed written ICF shall be read, signed, 
and dated by each patient prior to entering the trial or prior to performing any study procedure.  
The original signed and dated ICF will be kept on file at the study site.  Patients will be given a 
copy of the signed ICF and will be informed of any new developments during the course of the 
study that might influence their continued participation in the study. 
The Investigator or a qualified designee will be available to answer each patient’s questions 
throughout the study, and all questions must be answered to the patient’s satisfaction.  If the 
protocol is amended and a revised ICF is introduced during the study, each patient’s further 
consent must be obtained.  The new version of the ICF must be approved by the EC, prior to 
subsequently obtaining each patient’s consent. 
Receipt of written informed consent will be documented in each patient’s or potential patient’s 
CRF.  The signed ICF must remain in each patient’s study file and must be available for 
verification by study monitors at all times. 
Separate written, signed informed consent must be obtained if the patient is to participate in the 
optional pharmacogenomic assessment. 
 


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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 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 subjects/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 (SOPs) of the contract research organization (CRO).  The 
Investigator will assume the responsibility of ensuring the completeness and accuracy of the 
clinical data.  All data will be verified for quality control and will also be subject to audits from 
Tonix or designee to ensure quality. 


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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 which are validated and Part 11-compliant. 
The responsible clinical study monitor(s) will check data at the monitoring visits to the clinical 
study site.  The Investigator will ensure that the data collected are accurate, complete, and 
legible.  Any changes made to the clinical data will be documented with a full audit trail. 
Aspects of the clinical and statistical phases of the study, including all associated documentation 
may be reviewed by the Quality Assurance Unit of the contract research organization using a 
risk-assessment approach.  The final clinical and statistical report will be audited to ensure that, 
as far as can be reasonably established, the methods described and the results reported accurately 
reflect the raw data generated during the study. 
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 is collected via paper (patient questionnaires, etc.), the data must be entered into 
the eCRF 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 (e.g., written informed consent forms).  These 
records should be maintained by the Investigator in strict confidence except to the extent 
necessary to allow auditing by regulatory authorities, Tonix, or its agents.  These records should 
be kept in compliance with HIPAA regulations. 
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 towards the clinical development of the indicated 
investigational drug and may be disclosed by Tonix to regulatory authorities, other Investigators, 
corporate partners, or consultants as required. 
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 sixty (60) days before the expected date of submission for 
publication, unless otherwise arranged with Tonix in writing.  This will enable Tonix to protect 
its proprietary information and augment the publication with insights or information of which the 
Investigator may not be aware. 
Patient names and other identifiers, such as photographs or audio or video recordings, may not 
be disclosed in any publication or public forum without prior written authorization from the 
patients involved or their legal guardians.   


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19. 
LIST OF REFERENCES 
AMRIX® (cyclobenzaprine HCl) Prescribing Information. Teva Pharmaceuticals USA 
Inc.,updated April 2013; updated May 2018.  
Ahles T, Yunus M, Riley S, Bradley J, Masi A.  Psychological factors associated with primary 
fibromyalgia syndrome.  Arthritis Rheum 1984; 27:1101-1106. 
Bennett R, Clark S, Goldberg L, et al.  Aerobic fitness in patients with fibrositis: A controlled 
study of respiratory gas exchange and xenon clearance from exercising muscle.  Arthritis Rheum 
1989; 32:454-460. 
Bennett R, Gatter R, Campbell S, Andrews R, Clark S, Scarola J.  A comparison of 
cyclobenzaprine and placebo in the management of fibrositis.  Arthritis Rheum 1988; 31:1535-
1542. 
Burckhardt CS, Goldenberg D, Crofford L, Gerwin R, Gowans S, Jackson K, Kugel P, 
McCarberg W, Ruidn N, Schnaberg L, Taylor AG, Taylor J, Turk D.  Guideline for the 
Management of Fibromyalgia Syndrome. Pain in Adults and Children.  APS Clinical Practice 
Guideline Series No. 4.  Glenview, IL: American Pain Society, 2005. 
Campbell S, Clark S, Tindal E, Forchand M, Bennett R.  Clinical characteristics of fibrositis: A 
clinical “blinded” controlled study of symptoms and tender points [abstract].  Arthritis Rheum 
1982; 25 (Suppl):S4. 
Carette S, Bell MJ, Reynolds WJ, Haraoui B, McCain GA, Bykerk VP, Edworthy SM, Baron M, 
Koehler BE, Fam AG, Bellamy N, Guimont C.  Comparison of amitriptyline, cyclobenzaprine 
and placebo in the treatment of fibromyalgia: A randomized, double-blind clinical trial.  Arthritis 
Rheum 1994; 37:32-40. 
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999;55(3):853-7. 
FDA ‘The Voice of the Patient’ Report-, FDA’s Patient-Focused Drug Development Initiative 
Fibromyalgia Public Meeting on March 26, 2014 and Report dated October 2014. 
Fossaluzza V, De Vita S.  Combined therapy with cyclobenzaprine and ibuprofen in primary 
fibromyalgia syndrome.  Int J Clin Pharmacol Res 1992; 12 (2):99-102. 
Goldenberg DL, Burckhardt C, Crofford L.  Management of fibromyalgia syndrome.  JAMA 
2004 Nov 17; 292 (19):2388-2395. 
Häuser W, Thieme K, Turk DC.  Guidelines on the management of fibromyalgia syndrome: A 
systematic review.  Eur J Pain 2010 Jan; 14 (1):5-10. 
Keller A, McGarvey EL, Clayton AH. Reliability and construct validity of the Changes in Sexual 
Functioning Questionnaire short-form (CSFQ-14). J Sex Marital Ther. 2006 ;32(1):43-52.  
Lewis T, Kellgren J.  Observations relating to referred pain, visceromotor reflexes and other 
associated phenomena.  Clin Sci 1939; 4:47-71. 
Macfarlane GJ, Kronisch C, Dean LE, Atzeni F, Häuser W, Fluß E, Choy E, Kosek E, Amris K, 
Branco J, Dincer F, Leino-Arjas P, Longley K, McCarthy GM, Makri S, Perrot S, Sarzi-Puttini 


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P, Taylor A, Jones GT. EULAR revised recommendations for the management of fibromyalgia. 
Ann Rheum Dis. 2017; 76(2):318-328. 
Moldofsky H. Chronobiological influences on fibromyalgia syndrome: Theoretical and 
therapeutic implications. Ballières Clin Rheumatol 1994; 8:801-810. 
Payne T, Leavitt F, Garron D, et al.  Fibrositis and psychological disturbance.  Arthritis Rheum 
1982; 25:213-217. 
Quimby L, Gratwick G, Whitney C, Block S.  A randomized trial of cyclobenzaprine for the 
treatment of fibromyalgia.  J Rheumatol 1989; 16 (Suppl):140-143. 
Perrot S, Russell IJ. More ubiquitous effects from non-pharmacologic than from pharmacologic 
treatments for fibromyalgia syndrome: a meta-analysis examining six core symptoms. Eur J Pain. 
2014 ;18(8):1067-80. 
Reynolds W, Moldofsky H, Saskin P, Lue F.  The effects of cyclobenzaprine on sleep 
physiology and symptoms in patients with fibromyalgia.  J Rheumatol 1991; 18:452-454. 
Russell J.  Neurohormonal aspects of fibromyalgia syndrome.  Rheum DisNorth Am 1989; 
15:149-168. 
Santandrea S, Montrone F, Sarzi-Puttini P, Boccassini L, Caruso I.  A double-blind crossover 
study of two cyclobenzaprine regimens in primary fibromyalgia syndrome.  Intern Med Res 
1993; 21:74-80. 
Smythe H.  Fibrositis and other diffuse musculoskeletal syndromes.  In Kelley W, Harris E, 
Ruddy S, Sledge C, eds., Textbook of Rheumatology.  Philadelphia: Saunders, 1985. 
Wolfe F, Cathey M, Kleinheksel S, et al.  Psychological status in primary fibrositis and fibrositis 
associated with rheumatoid arthritis.  J Rheumatol 1984; 11:500-506. 
Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, et al.  The American College of 
Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom 
severity.  Arthritis Care Res 2010; 62(5):600-10. 
Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Häuser W, Katz RL, Mease PJ, Russell 
AS, Russell IJ, Walitt B. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. 
Semin Arthritis Rheum. 2016 ;46(3):319-329. 
Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L.  The prevalence and characteristics of 
fibromyalgia in the general population.  Arthritis Rheum 1995 Jan; 38(1):19-28. 
 
 
  
 


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20. 
APPENDICES 
APPENDIX 1  
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 Sept. 26, 2016).  Excluded strong CYP3A4 inhibitors are listed in the far left column of 
the table.  
 
Strong Inhibitors  
 
≥ 5-fold increase in AUC   
Or, > 80% decrease in CL  
Moderate Inhibitors   
 
≥ 2 but < 5-fold increase in AUC   
Or 50-80% decrease in CL  
Weak Inhibitors  
 
≥ 1.25 but < 2-fold increase in 
AUC   
Or, 20-50% decrease in CL  
CYP3A4  
boceprevir  
clarithromycin   
cobicistat  
conivaptan  
danoprevir  
(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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APPENDIX 2  
AMRIX® Package Insert (DATED April 2019) 
 
 


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SAP_001.pdf: 
Tonix Pharmaceuticals, Inc. • 26 Main Street, Suite 101 Chatham, NJ 07928 • Tel: 862.904.8182  
 
          
 
 
 
 
 
TNX-CY-F304  
 
A PHASE 3, DOUBLE-BLIND, RANDOMIZED, 
MULTICENTER, PLACEBO-CONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF TNX-102 SL 
TAKEN DAILY AT BEDTIME IN PATIENTS WITH 
FIBROMYALGIA  
“RELIEF STUDY”  
 
 
Document Date: 16 OCTOBER 2020  
 
NCT04172831 


CONFIDENTIAL 
Page 1 
16OCT2020 
 
Statistical Analysis Plan 
 
Protocol Title: TNX-CY-F304 
A PHASE 3, DOUBLE-BLIND, RANDOMIZED, MULTICENTER, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF TNX-102 SL TAKEN DAILY AT BEDTIME IN 
PATIENTS WITH FIBROMYALGIA (RELIEF STUDY) 
Protocol Number: Protocol No. TNX-CY-F304, Amendment 02 (27 March 2020) 
Investigational 
Product: 
TNX-102 SL (cyclobenzaprine HCl sublingual tablets) 
Phase: 3 
Sponsor: Tonix Pharmaceuticals, Inc. 
509 Madison Avenue, Suite 1608 
New York, NY 10022 
SAP Author: 
 
 
 
SAP Version: Final Version 2.0 
SAP Date: 16 Oct 2020 
CONFIDENTIAL 


 
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DOCUMENT HISTORY 
Version 
Date 
Author 
Description 
1.0 
 
 
 
1.0 
 
 
 
2.0 
16 Oct 2020 
 
 
 
 


 
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SIGNATURE PAGE AND APPROVALS 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Date 


 
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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 Exploratory Endpoints ...................................................................10 
3.2.3 Safety Endpoints ............................................................................11 
4. 
OVERALL STUDY DESIGN AND PLAN .......................................................12 
4.1 
Selection of Study Population ....................................................................13 
4.2 
Method of Treatment Assignment and Randomization .............................13 
4.3 
Treatment Blinding ....................................................................................13 
4.4 
Minimization of Missing Data ...................................................................14 
4.4.1 Opioid Usage .................................................................................14 
4.4.2 Intermittent Missing Data ..............................................................14 
5. 
ANALYSIS AND REPORTING ........................................................................15 
5.1 
Interim Analysis .........................................................................................15 
5.2 
Final Analysis ............................................................................................15 
6. 
SAMPLE SIZE DETERMINATION .................................................................17 
7. 
ANALYSIS POPULATIONS .............................................................................18 
8. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ..................................19 
8.1 
General Statistical Methodology................................................................19 
8.1.1 Adjustments for Multiplicity and Other Alpha Control .................19 
8.1.2 Data Handling for Subjects Who Withdraw/Drop Out from the Study
........................................................................................................20 
8.1.3 Imputation of Missing Data ...........................................................21 


 
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8.2 
Efficacy Assessments.................................................................................22 
8.2.1 Average Daily Pain Score ..............................................................22 
8.2.2 Average Daily Sleep Quality Score ...............................................23 
8.2.3 Patient Global Impression of Change (PGIC) ...............................24 
8.2.4 Revised Fibromyalgia Impact Questionnaire (FIQR) ....................24 
8.2.5 Patient Reported Outcomes Measurement System (PROMIS) 
Instruments .....................................................................................24 
8.2.6 Changes in Sexual Functioning Questionnaire Short-Form (CSFQ-14)
........................................................................................................25 
8.3 
Safety Endpoints ........................................................................................25 
9. 
STUDY SUBJECTS AND DEMOGRAPHICS.................................................27 
9.1 
Disposition of Subjects and Withdrawals ..................................................27 
9.2 
Protocol Violations and Deviations ...........................................................27 
9.3 
Demographics and Other Baseline Characteristics ....................................27 
10. 
EFFICACY ANALYSES ....................................................................................28 
10.1 
Primary Efficacy Analysis .........................................................................28 
10.1.1 Estimand ........................................................................................28 
10.1.2 Primary Analysis ............................................................................28 
10.1.3 Sensitivity Analyses .......................................................................29 
10.2 
Secondary Efficacy Analyses ....................................................................30 
10.3 
Exploratory Analyses .................................................................................30 
10.3.1 Exploratory Analyses of Daily Pain Scores ...................................32 
10.4 
Analyses by Dose .......................................................................................33 
11. 
SAFETY AND TOLERABILITY ANALYSES ................................................34 
11.1 
Adverse Events ..........................................................................................34 
11.1.1 Adverse Events Leading to Discontinuation of Study Drug ..........35 
11.1.2 Serious Adverse Events .................................................................35 
11.1.3 Oral TEAEs ....................................................................................35 
11.1.4 Deaths .............................................................................................35 
11.2 
Clinical Laboratory Evaluations ................................................................35 
11.3 
Columbia Suicide Severity Rating Scale (C-SSRS) ..................................36 
11.4 
Vital Signs ..................................................................................................36 
11.5 
Physical Examination and Oral Cavity Exam ............................................37 


 
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12. 
MEDICATIONS ..................................................................................................38 
12.1 
Concomitant Medication ............................................................................38 
12.2 
Opioid Medications ....................................................................................38 
12.3 
Exposure and Compliance .........................................................................38 
13. 
CHANGES FROM PLANNED ANALYSIS .....................................................40 
14. 
REFERENCES (AVAILABLE UPON REQUEST) .........................................41 
15. 
APPENDICES ......................................................................................................42 
15.1 
Appendix A ................................................................................................42 
15.2 
Appendix B ................................................................................................43 
15.3 
Appendix C ................................................................................................44 
15.4 
Appendix D ................................................................................................45 
15.5 
Appendix E ................................................................................................46 
15.5.1 General Reporting Conventions .....................................................46 
15.5.2 Population Summary Conventions ................................................47 
 


 
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ABBREVIATIONS 
ABBREVIATION 
DEFINITION OR DESCRIPTION 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical (WHO Drug Classification System) 
BDI-II 
Beck Depression Inventory II 
BMI 
Body Mass Index 
CFB 
Change from Baseline 
CRF 
Case Report Form 
CSFQ-14 
Changes in Sexual Functioning Questionnaire Short-Form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EMA 
European Medicines Agency 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FIQR 
Fibromyalgia Impact Questionnaire (Revised) 
FM 
Fibromyalgia 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
ITT 
Intent-to-Treat 
IVRS 
Interactive Voice Response System 
LOE 
Loss of efficacy 
MAR 
Missing at random 
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 subjects 
NRS 
Numeric Rating Scale 
PGIC 
Patient Global Impression of Change 
PROMIS 
Patient Reported Outcomes Measurement Information System  
RHNP 
Randomization Honoring Non-Parametric 
REML 
Restricted Maximum Likelihood 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SF 
Short Form 
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-F304 Study has been written 
 
for the Phase 3 AFFIRM study (Protocol No.TNX-CY-F301/AFFIRM).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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2. OVERVIEW 
This SAP describes the planned analysis and reporting for Protocol TNX-CY-F304 (A Phase 3, 
Double-Blind, Randomized, Multicenter, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of TNX-102 SL Taken Daily at Bedtime in Patients with Fibromyalgia).  
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA, European Medicines Agency (EMA), and International Council for 
Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human 
Use: Guidance on Statistical Principles in Clinical Trials.  All work planned and reported for this 
SAP will follow internationally accepted guidelines for statistical practice, as published by the 
American Statistical Association and the Royal Statistical Society. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts.  Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data.  Any post-
hoc, or unplanned exploratory analysis performed will be clearly identified as such in the final 
CSR. 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
The reader of this SAP is encouraged to also read the clinical protocol, and other identified 
documents, for details on the planned conduct of this study.  Operational aspects relating to 
collection and timing of planned clinical assessments are not repeated in this SAP unless they are 
relevant to the planned analysis. 
 
 


 
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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 taken at bedtime over 14 weeks 
of treatment using an 11-point (0-10) numerical rating scale (NRS). 
3.1.2 Secondary Objectives 
The secondary objective is to evaluate the safety of TNX-102 SL taken at bedtime over 14 weeks 
of treatment. 
3.2 Study Endpoints 
3.2.1 Efficacy Endpoints 
The primary efficacy endpoint is:  
• Change from Baseline to the Week 14 endpoint in the diary NRS weekly average of daily 
self-reported average pain severity scores. 
 
Key secondary efficacy endpoints include: 
• Proportion of subjects with a Patient’s Global Impression of Change (PGIC) rating of “very 
much improved” or “much improved” at the Week 14 endpoint 
• Change from baseline in the Fibromyalgia Impact Questionnaire – Revised (FIQR) 
symptoms domain score at the Week 14 endpoint 
• Change from baseline in the FIQR function domain score at the Week 14 endpoint 
• Change from baseline in the Patient Reported Outcomes Measurement Information System 
(PROMIS) score for sleep disturbance at the Week 14 endpoint 
• Change from baseline in the PROMIS score for fatigue at the Week 14 endpoint 
• Change from baseline in the weekly average of the daily diary assessment of sleep quality at 
the Week 14 endpoint 
3.2.2 Exploratory Endpoints 
Exploratory efficacy endpoints include: 
• Proportion of subjects with a ≥30% improvement from baseline to Weeks 1-14 in the daily 
self-reported pain severity score  
• Proportion of subjects with a ≥50% improvement from baseline to Weeks 1-14 in the daily 
self-reported average pain severity scores 
• Proportion of subjects with a PGIC rating of “very much improved” or “much improved” at 
all post-randomization clinic visits 
• Mean PGIC rating at all post-randomization clinic visits 


 
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• Change from baseline in the FIQR total score, overall impact domain score, and individual 
item scores at all post-randomization clinic visits 
• Change from baseline in the FIQR symptoms domain score and function domain scores at all 
post-randomization clinic visits 
• Change from baseline in the PROMIS score for sleep disturbance at all post-randomization 
clinic visits 
• Change from baseline in the PROMIS score for fatigue at all 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 self-reported average pain severity 
scores at Weeks 1-14 
• Changes from baseline in patient-rated Changes in Sexual Functioning Questionnaire Short-
Form (CSFQ-14) in females and in males, analyzed separately 
• Change from screening in the in-clinic assessment of pain (24-hour & weekly recall) 
 
3.2.3 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), and 
the monitoring of depression status via the Beck Depression Index (BDI-II). 
 
 


 
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4. OVERALL STUDY DESIGN AND PLAN 
This is a Phase 3, 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 
daily at bedtime for the management of fibromyalgia.  The study is being conducted at 
approximately 35-45 investigational sites in the United States (US). 
The study will consist of a Screening Visit (Visit 1, Days −35 to −8), a washout period and 
screening period of at least 7 days (for those subjects not requiring washout) and no more than 
35 days, inclusive of a 7-day baseline data collection phase immediately preceding the Baseline 
visit. For extenuating circumstances, the duration of the screening period may be increased up to 
49 days with Medical Monitor approval. Note, this trial was ongoing at the time the SARS-CoV-
2 virus began to spread in the US, leading to the illness known as COVID-19 that is part of the 
COVID-19 pandemic. Due to the exceptional circumstances caused by the COVID-19 pandemic, 
an option for a telephone visit was made available for Weeks 2, 6, 10 (Visit 3, 4, 5), and, only 
with Medical Monitor approval, Week 14/Visit 6 (or Early Termination) for those unable to 
attend an in-clinic visit due to the COVID-19 pandemic. 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 Early Termination), a home visit should be conducted rather than a telephone visit 
in order to collect greater safety data than the telephone visits allow. The Screening phase will be 
followed by the Baseline/Randomization Visit (Visit 2, Day 1), and 4 treatment visits at Weeks 
2, 6, 10, and 14 (or early termination).  The total duration of the study, including Screening, will 
be approximately 15-21 weeks.  The maximum treatment duration will be 14 weeks. 
Eligible subjects who provide written informed consent will have study assessments performed 
at Screening and will stop all excluded medications during the washout period through the Week 
14 visit (Visit 6).  Subjects will record their average pain intensity for the previous 24 hours in 
the evening every day from Visit 1 through Visit 6 on an electronic diary system.  After 
recording Baseline Diary scores for at least 7 days, subjects will return to the investigative site 
for Baseline assessments and randomization (Day 1), where they will be randomly assigned to 
receive TNX-102 SL or matching placebo sublingual tablets in a 1:1 ratio.  Subjects will take the 
study drug sublingually daily at bedtime, starting on the day that they are randomized (Day 1), 
for 14 weeks. For the first two weeks of treatment, subjects will start on TNX-102 SL 2.8 mg (1 
tablet) or placebo. At the Week 2 visit (Visit 3), all subjects will have the dose increased to 
TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or 2 placebo tablets.  Subjects will return to the site for 
assessment of efficacy and safety, as well as dose tolerability, at Weeks 6, 10, and 14 (or early 
termination), unless a telephone visit is conducted, in which case certain assessments that cannot 
be done over the phone (e.g. vitals and oral cavity exam) are allowed to be omitted, which is 
specifically stated in the protocol. In scenarios in which 5.6 mg dose is considered intolerable 
and would otherwise lead to study discontinuation, the Investigator may lower the dose back to 
TNX-102 SL 2.8 mg or one placebo per day.  Re-challenge with TNX-102 SL 5.6 mg or 2 
placebo tablets may be attempted at a later date if/when it is deemed clinically warranted by the 
Investigator, or the subject may remain on the lower 2.8 mg dose for the remainder of the study.  
Subjects who wish to withdraw from the study may do so at any time. 
Subjects will be trained on use of the diary system at the Screening visit.  Each evening, when 
the subject utilizes the diary, the system will prompt the subject regarding daily average pain 


 
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intensity and sleep quality from the previous night, and, starting Day 2 post-randomization, 
regarding study drug dosing the previous night. 
At Screening Visit 1 and after signing the written informed consent, any required washout should 
be discussed with the subject and plans made for an appropriate schedule for reducing/stopping 
any excluded medications.  This down titration and medication withdrawal must be 
accomplished so that the subject is medication-free for at least 21 days prior to randomization.  
This will provide 14 days off the excluded medication before the subject starts the 7-day run-in 
phase during which critical baseline daily diary efficacy data are collected.  Any additional time 
required for down-titration would be in addition to this 21-day washout requirement.  For this 
reason, subjects can remain in screening for up to 35 days, which provides an additional 2 weeks 
for down-titration, if required. 
4.1 Selection of Study Population 
For a complete list of inclusion and exclusion criteria please refer to the study protocol 
referenced on page 1. 
4.2 Method of Treatment Assignment and Randomization 
The following randomization criteria must be satisfied at the Baseline visit (Visit 2) in order for 
the subject to continue in the study and be randomized: 
1. The subject continues to meet all inclusion and exclusion criteria, including urine and 
blood test results and is successfully and consistently utilizing the diary system. 
2. The subject’s FM diary pain ratings satisfy the following criteria, as assessed by diary 
pain scores (24-hour recall): 
a. A mean 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 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. Pain scores must be recorded on at least 5 out of the 7 days immediately 
preceding Visit 2. 
 
Before the start of the study, a computer-generated randomization schedule will be prepared.  
Based on the randomization schedule, eligible subjects will be randomly assigned in a 1:1 ratio 
to receive TNX-102 SL tablets or placebo tablets for 14 weeks. 
 
Treatment A:     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 each day at bedtime. 
Treatment B: 
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. 
4.3 Treatment Blinding 
This is a double-blind study.  Unless otherwise specified, all study personnel are to remain 


 
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blinded to study drug.  With the exception of unblinded CRO staff performing the interim 
analysis and IDMC members, treatment assignments will not be revealed until all subjects 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 subject to discontinue study drug; however, the investigator should not be 
unblinded unless it is imperative for the subject’s overall safety to determine whether the subject 
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, 
investigators have the option after the Week 2 visit when dose escalation has occurred, to reduce 
the treatment dose back to one tablet of TNX-102 SL 2.8 mg or one tablet of placebo if the 
higher dose is resulting in tolerability issues that would otherwise lead to discontinuation in the 
study.  The importance of minimizing the amount of missing data will be discussed with all 
study investigators, and their awareness of the importance of subject compliance and minimal 
dropout rates is factored into their recruiting plans and daily subject management.  In addition, 
investigators are advised to contact the medical monitor for guidance on available management 
options when needed to avoid subjects withdrawing from the study. 
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 subject 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 
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.   
A listing of concomitant medication CRF data identifying the use of opioids will be reviewed by 
the project team and approved by the Sponsor prior to database lock and unblinding, and will be 
used to flag records in the analysis database and in the by-subject concomitant medication 
listings. These flagged records will also be utilized to identify records to be censored in the 
sensitivity analysis described in Section 10.1.3. 
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). 


 
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5. ANALYSIS AND REPORTING 
5.1 Interim Analysis 
An optional interim analysis may 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 
 
• Increase the sample size by a fixed amount 
• Keep the current sample size and continue as planned 
• Stop the study early for futility 
 
 
 
 
 
 
 
 
 
 
 
 
 
The interim analysis will be conducted approximately 18 weeks after randomization of 
approximately 236 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 futility or efficacy, initial results may be released prior to full 
database lock; however, clinical study report (CSR) results will be based on the final analysis 
described below. 
 
 
5.2 Final Analysis 
All final, planned analyses will be performed after the last subject 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 


 
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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. 
 
 


 
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6. SAMPLE SIZE DETERMINATION 
The study is planned to enroll approximately 470 subjects total in a 1:1 randomization, that is, 
235 subjects in each of the TNX-102 SL and placebo arms. 
 
 
 
 
The interim analysis will re-evaluate these assumptions and the IDMC may recommend a 
sample size increase.  
 


 
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7. ANALYSIS POPULATIONS 
The following analysis populations are planned for this study: 
• Safety Population (SAFETY): all subjects who took investigational product. Subjects 
that were issued study drug, but do not return all of it will be included in the safety 
population. All safety analyses and demographic/baseline characterization will be 
performed using this population, analyzed as treated. 
• Intention-To-Treat Population (ITT): all subjects who were randomized.  This is the 
primary population for efficacy analyses, and subjects will be analyzed based on their 
randomized treatment. 
• Interim Population: approximately the first 235 subjects randomized; this will be 
utilized for the interim analysis, if performed.   In the case of an early stop, this will serve 
as the population for efficacy analyses.  The cutoff of the population will be the date that 
the 235th subject is randomized; thus it is possible to have a marginal overrun depending 
on the number of subjects randomized that day. 
• Early Stop Safety Population: all subjects that are in the safety population and the 
interim population.  This will serve as a population parallel to the Interim Population for 
the purpose of evaluating the risk/benefit on the same sample. 
 
 
 


 
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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 subjects for a 
population in each treatment group will be grouped together; subjects 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 subjects in the active arm with a 
dose reduction at any point in the study, summary statistics on key outcomes may be reported for 
subjects 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 subjects (N) with non-
missing values, mean, standard deviation, median, minimum, and maximum. 
Categorical, qualitative variable summaries will include the frequency and percentage of subjects 
who are in the particular category.  In general, the denominator for the percentage calculation 
will be based upon the total number of subjects 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. 
Study day is defined as assessment date – first dose date +1. 
All analyses will be performed using SAS® Software version 9.3 or later. 
8.1.1 Adjustments for Multiplicity and Other Alpha Control 
8.1.1.1 Alpha Spend, Early Stops and Sample Size Increase 
 
 
 
 
  
Under both cases (early stop for efficacy, study continues to full enrollment), the alpha 
adjustment being applied to the primary will also be utilized as the criteria for the key secondary 
outcomes. 
Likewise, in the case of a sample size increase, the same inverse-normal method described in the 
primary efficacy analysis will be applied to the key secondary analyses to adjust the reported p-
value; these will be tested with the adjusted alpha to account for the first stage alpha spend. 


 
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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 
 level, a significance level of 
 
will be used for comparing the secondary endpoints in an ordered fashion.  If the analysis for a 
secondary endpoint does not produce a statistically significant result (
), then the 
remaining secondary endpoint analyses will automatically be considered non-significant 
regardless of the p-value produced.   
 
 
The order of key secondary endpoints in which they are to be tested is as follows: 
• Proportion of subjects with a PGIC rating of “very much improved” or “much improved” 
at Week 14 
• Change from baseline in the FIQR symptoms domain score at Week 14 
• Change from baseline in the FIQR function domain score at Week 14 
• Change from baseline in the PROMIS score for sleep disturbance at Week 14 
• Change from baseline in the PROMIS score for fatigue at Week 14 
• Change from baseline to Week 14 in the weekly average of the daily diary assessment of 
sleep quality. 
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 Subjects Who Withdraw/Drop Out from the Study 
Subjects 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), 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 subject 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 subject without valid Week 10 data who early terminates on 
Day 79 would have the Day 79 data analyzed with the Week 10 data. 
Subjects 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 subject 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 


 
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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. 
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. 
Missing weekly pain scores for participants in the ITT population will be imputed via multiple 
imputation (MI).  When the study medication was discontinued due to lack of efficacy (LOE) or 
due to an AE, missing values will be imputed drawing from the baseline values, conditioned on 
the non-missing weekly average post-baseline values, of all participants in the ITT population 
under the assumption that they are missing not at random (MNAR), with a covariate for site.  If 
the study medication was discontinued for any other reason (including impacts from the COVID-
19 pandemic), values will be imputed within treatment group using MI under the assumption that 
they are missing at random (MAR) with covariates for site and the average pain severity score 
recorded at each time point.  The MAR approach will also be applied for sporadic missing values 
(prior to discontinuation).   The MI process will use twenty repeats in the analysis datasets 
generated; seeds are given in Appendix D.  For the purposes of the MI, all sites with less than 10 
subjects will be pooled into a single large site; this will be done for both the interim and post 
interim samples. 
The steps will be as follows: 
1. Intermittent missing weekly average scores will first be imputed using the Markov Chain 
Monte Carlo (MCMC) method implemented with the SAS MI procedure, which is 
appropriate for non-monotonic missing data.  
2. For subjects that do not discontinue for LOE or AEs, a MAR imputation will be applied: 
the monotone missing values will then be multiply imputed with the SAS MI procedure 
using the monotone regression method. Baseline average and the weekly scores will be 
included as covariates as well as site; imputation will be done within treatment group. 
3. For subjects that discontinue for LOE or AEs, an iterative process will be applied moving 
through each week. The complete MAR dataset from step 2 above will be used and 
augmented with subjects missing for the week being imputed at that stage.  The non-
missing values for the week in question will temporarily be set to the subjects 
corresponding baseline value, so the data from LOE and AE subjects are imputed for that 
week drawing from the baseline distribution. This will proceed from Week 1 to Week 14 
with the imputed complete dataset for a week serving as the basis for the subsequent 
week.  Covariates at each stage will include the values for the prior weeks (observed, 
MAR imputed in steps 1& 2, or imputed previously in this step) and site. 
The above process will be done independently for the subjects included in the interim analysis 
and those not in the interim. 
Daily sleep diary data will be handled in an identical manner to the pain scores. 


 
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Continuous outcomes included in the list of key secondary outcomes that are collected in-clinic 
will be handled as above, minus the step of creating weekly averages of daily values and with 
steps being done by visit instead of week. 
Subjects with missing PGIC at a given visit will be considered non-responders at that visit for the 
purposes of treatment comparisons and efficacy claims; additional tabulations will summarize 
the number and percentage in each category out of non-missing values as well as a count of the 
missing values. 
No missing safety data will be imputed. 
8.2 Efficacy Assessments 
8.2.1 Average Daily Pain Score 
The average daily pain score will be obtained using the daily, 24-hour recall, NRS pain data 
collected with the diary system. Since a mean is used in the calculation of the primary endpoint, 
it is not necessary to replace values missing on random intermittent days. 
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 days immediately 
preceding the baseline visit in order for the subject to qualify for randomization. 
The mean of the daily, subject 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 
subject 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, subjects 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, subjects 
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 subject 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.  Subjects 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 C.   
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 


 
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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 subjects 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 
subject 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 subjects that continue to 
fill out the diary into Week 14 and beyond will have non-missing values for the Week 14 
timepoint for diary outcomes.  Day 106 will be the last allowable day to be included in the 
average.  
Week 
Nominal Study 
Day Intervals 
Baseline 
Day -7 to -1 
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 Average Daily Sleep Quality Score 
The average daily sleep quality score will be obtained in the same manner as the average daily 
pain 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, 
subjects report their sleep starting the first night that they take randomized drug through the night 


 
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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 Patient Global Impression of Change (PGIC) 
PGIC is a question completed by the subject at Weeks 2, 6, 10, and 14.  The subject will rate the 
change in their overall fibromyalgia symptoms 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 PGIC 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 PGIC score will be considered 
a non-responder for that visit. 
8.2.4 Revised Fibromyalgia Impact Questionnaire (FIQR) 
The FIQR is made up of 3 domains: (1) functional (9 questions); (2) overall impact (2 questions) 
and (3) symptoms (10 questions).  If 2 or more items are missing from the functional domain, the 
domain will be considered invalid for that visit.  Likewise, if any item is missing from the overall 
impact domain or the symptom domain, those domains will be considered invalid. 
To account for missing items in the functional domain, the score will be recalculated as: 
New score = (Raw score / # of items answered) × # of items in domain 
 
The FIQR total score can be determined after all domain scores have been calculated using the 
following steps.  First, divide the function domain score by 3, divide the overall impact domain 
score by 1, and divide the symptom domain score by 2.  Next, add the three resulting domain 
scores to obtain the total score of FIQR. If any domain score is missing, then the total is missing. 
8.2.5 Patient Reported Outcomes Measurement System (PROMIS) Instruments 
8.2.5.1 PROMIS Short-Form (SF) Fatigue and Sleep Disturbance Instruments 
The PROMIS Short-Form Fatigue and Sleep Disturbance 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.  Either 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 
and Appendix B for Sleep Disturbance. 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. 


 
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8.2.6 Changes in Sexual Functioning Questionnaire Short-Form (CSFQ-14) 
The CSFQ-14 (Keller et al. 2006) is validated scale with internal reliability designed to allow a 
patient to self-evaluate his or her sexual behaviors or problems in a number of areas.  The CSFQ-
14 will be administered at Baseline (Visit 2) and Week 14/ET (Visit 6).  It yields a total score, 
three subscales corresponding to phases of the sexual response cycle (i.e. desire, arousal, 
orgasm), and five subscales corresponding to important dimensions of sexual functioning.  It is 
considered a useful scale for assessing sexual side effects of medications.  For all items, higher 
scores reflect higher sexual functioning.  For 12 of the 14 items, higher sexual functioning 
corresponds to greater frequency or enjoyment/pleasure (e.g. 1=never to 5 = every day).  For two 
items (item 10, assessing loss of interest after arousal for women and priapism for men, and item 
14, assessing painful orgasm), higher sexual functioning corresponds to lower frequency (e.g. 
1=every day; 5=never). Items 10 and 14 are included in the total score but not in any subscale 
scores. 
 
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: 


 
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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 SUBJECTS AND DEMOGRAPHICS 
9.1 Disposition of Subjects and Withdrawals 
The numbers and percentage of subjects 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 subjects in each analysis population will be 
reported.  Additionally, the number and percentage of subjects 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 subjects who have data entered into 
the database. 
9.2 Protocol Violations and Deviations 
Protocol deviations will be checked on complete data for all subjects.  Protocol deviations will be 
summarized by type, status as major vs minor, and by treatment group for the Safety population. 
Individual subjects 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 subjects 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, BMI, family status, 
education and employment status) 
• Tobacco/nicotine, alcohol, and THC/cannabis use history 
• ACR Criteria 
 
Medical History will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.1 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 
The primary ITT analysis will provide an estimate of the following causal estimand:  the 
difference in the weekly mean change from Baseline of the daily subject self-reported 24-hour 
recall average pain severity rating using an 11-point (0-10) NRS evaluated at the Week 14 
endpoint in all randomized subjects attributable to the initially randomized treatment assignment, 
under the assumption that those withdrawing due to AEs and lack of efficacy revert to the 
baseline pain levels (on average).   
10.1.2 Primary Analysis 
An adaptive group sequential design will be performed by an independent third party statistical 
group 
 to cover an early efficacy stop, sample size adjustment, or futility stop; the final 
CSR analyses in all cases will be performed by 
(the primary biostatistics vendor). To assure 
independence of the stage wise test statistics, the first stage population is defined as the first half 
of the subjects randomized, planned as 236. The second stage population is defined as all 
subjects randomized after the interim cut-off.  
 
The interim analysis will be executed once all subjects in the Interim Population either drop out 
or reach Week 14.  
 
If the study is stopped early for efficacy, subjects who were randomized after the interim cut off 
will not be included in the efficacy analyses. For early stop, safety analyses will be reported both 
on all subjects exposed (the Safety Population) and all subjects exposed in the Interim Population 
(Early Stop Safety Population). 
Data of different stages will be combined using the inverse normal method to test the null 
hypotheses that there is no difference in the change from weekly average of daily pain between 
TNX-102 SL and placebo treatment groups at Week 14: (Cui 1999): 
 
𝑍1  = 𝛷−1(1 − 𝑝1) 
𝑎𝑛𝑑 𝑍2  = 𝑤1𝑍1 + 𝑤2𝛷−1(1 − 𝑝2)  
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-value 
p2 =the second stage p-value based on second stage participants 
For maximum statistical efficiency, the weights are defined prospectively according to the 


 
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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. The calculation of these weights is fixed and 
will not be changed due to unblinded data and is hence in line with the draft guidance on 
adaptive design clinical trials (CDER, CBER, February 2010). In order to control the type-I 
error, adaptive changes of the stage wise sample sizes will not lead to changes of the weights 
(Lehmacher & Wassmer 1999). 
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 with data imputed using multiple 
imputation (see Section 8.1.3). Week 14 will serve as the primary time point of interest.  Models 
will be run on each of the twenty imputation sets individually and will include the fixed, 
categorical effects of treatment, site, 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-subject 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. LS means and 
differences across the twenty MI reps 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. 
 
 
10.1.3 Sensitivity Analyses 
Four sensitivity analyses will be performed:   
For the first, pain scores will be censored on the day(s) on which an opioid is utilized.  If the 
subject utilizes an opioid for any indication, then the pain score on each impacted day will be 
replaced by the score obtained on the day immediately prior to the first day of opioid use (and 
until the opioid is no longer used).  This will be done prior to the weekly averaging, and all other 
calculations will be performed as described in the primary. This will investigate whether use of 
concomitant opioids influences the interpretation of study results. 
For the second, subjects that discontinue due to “withdrawal of consent” or “investigator 
decision” will be grouped with the LOE and AE dropouts when performing the multiple 
imputation procedure.  This analysis will investigate whether the categorization of these reasons 
for dropout influences the interpretation of study results. 
For the third, ALL subjects that discontinue will be grouped with the LOE and AE dropouts 
when performing the multiple imputation procedure.  This analysis will sample from the baseline 
distribution of all dropouts and will investigate whether treating dropouts as treatment failures 
(on average) influences the interpretation of study results. 
Finally, a tipping point analysis will be performed on the values for the primary analysis.  A shift 
parameter will be applied to the active treatment arm starting at .25 and increasing in increments 
of .25 through either 5 or when the outcome is no longer significant.  This will only be 
performed if the primary analysis is significant.  This will test the overall robustness of the 


 
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primary analysis. 
10.2 Secondary Efficacy Analyses 
Secondary efficacy analyses will be based on the ITT population only. 
 
Continuous 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 8.1.3 for the imputation algorithm and Section 10.1.2 for the analysis 
approach. 
Outcomes using these analyses will include: 
• Change from baseline in the FIQR symptoms domain score 
• Change from baseline in the FIQR function domain score  
• Change from baseline in the PROMIS score for sleep disturbance 
• Change from baseline in the PROMIS score for fatigue 
• Change from baseline in the weekly average of the daily diary assessment of sleep 
quality. 
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. 
For the sleep quality assessment collected via a daily subject diary, the baseline score and the 
weekly scores for each subject will be calculated as the weekly average score based on the mean 
of the scores recorded for that study week (Section 8.2.2). 
This will be repeated on the outcomes above, but using observed data only without imputation. 
Categorical Endpoints 
A categorical analysis of PGIC will be performed using a logistic regression model for each 
week with effects for treatment and investigative site.  If the model does not converge, site will 
be removed from the model.  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.  In addition, odds 
ratios and corresponding 95% CI intervals for being “very much improved” or “much improved” 
versus all other categories will be presented.  A summary of frequency counts for PGIC 
responses for each time point will be presented; Week 14 is of primary interest and all other time 
points are considered exploratory. 
10.3 Exploratory Analyses 
All efficacy analyses at time points other than Week 14 are considered exploratory as described 
above. 
 
Additional exploratory efficacy endpoints include: 


 
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• FIQR total score, overall impact domain score, and individual item scores at all post-
randomization clinic visits 
• Proportion of subjects with a ≥30% improvement from baseline to Weeks 1-14 in the daily 
self-reported pain severity score  
• Proportion of subjects with a ≥50% improvement from baseline to Weeks 1-14 in the daily 
self-reported average pain severity scores 
• PGIC as a continuous variable with 1-7 scoring 
• CSFQ-14 at Week 14 
• In-clinic assessment of pain (24-hour & weekly recall) 
• Permutation test of change from baseline in the weekly average of the daily pain scores at 
week 14. 
 
The proportion of improvement endpoints will be analyzed in using a logistic regression model 
for each week with effects for treatment and investigative site.  If the model does not converge, 
site will be removed from the model.  Subjects with missing data will be considered non-
responders.  In addition, odds ratios and corresponding 95% CI intervals for being a pain 
responder will be presented. 
 
In addition to the responder analysis in the secondary outcomes, PGIC will be analyzed as a 
continuous variable scoring the responses 1-7.  Results will be reported by treatment with 
summary statistics and an MMRM Model will be used to compare treatments.  The model will 
include the fixed, categorical effects of treatment, site, study week, and treatment by study week 
interaction.  An unstructured covariance structure will be used to model the within-subject 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. Significance testing 
will be based on least-squares means using a two-sided alpha=0.05 test and two-sided 95% 
confidence intervals will be presented. 
 
The CSFQ-14 is completed at baseline and Week 14/ET. It has a male and a female version, 
which will be analyzed separately.  The CSFQ-14 will be analyzed for its total score, three 
subscales on phases of sexual response, and five subscales for dimensions of sexual functioning 
by using an Analysis of Covariance (ANCOVA) model.  The model will include the fixed, 
categorical effects of treatment and site, plus a baseline covariate corresponding to the subscale 
(or total) being analyzed. Significance testing will be based on least-squares means using a two-
sided alpha=0.05 test and two-sided 95% confidence intervals will be presented.  This outcome is 
considered to be supportive of the product’s safety; other exploratory analyses are for further 
support of product efficacy. 
 
The FIQR exploratory endpoints and the in-clinic pain assessments will be analyzed using an 
MMRM including the fixed, categorical effects of treatment, site, study week, and treatment by 
study week interaction, as well as the fixed covariates of baseline value and baseline value score-


 
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by-study week interaction.  An unstructured covariance structure will be used to model the 
within-subject 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.  
Note that the screening values will be used as baseline for the in-clinic pain outcomes. 
 
10.3.1 Exploratory Analyses of Daily Pain Scores 
Randomization Honoring Non-Parametric (RHNP) hypothesis test. 
In this exploratory analysis, the primary endpoint of Week 14 change from baseline in daily pain 
scores will be analyzed by a RHNP method for computing p-values for the hypothesis that 
treatment has no effect. 
Subjects will be randomly reassigned to treatment 10,000 times using the original randomization 
algorithm, in the order subjects actually enrolled, using the original block sizes and 
randomization strata. The apparent effect of the treatment under each of these hypothetical 
assignments will be compared to the apparent effect for the actual assignment, approximating the 
distribution of the apparent treatment effect under the null hypothesis that treatment makes no 
difference whatsoever.   
The apparent effect size for each random allocation will be quantified by the median difference 
between the responses of subjects assigned to treatment by that allocation and those assigned to 
placebo by that allocation.  
The test statistic will be calculated for 10,000 random allocations and for the original observed 
data with actual treatment codes.  The percentile rank of the statistic for the true treatment 
assignment among the distribution of the statistics for the permutations is one-sided p-value for 
an exact randomized test of the null hypothesis that treatment makes no difference 
whatsoever.  If treatment assignment had no impact, the test statistic for the original observed 
data would be unlikely to be in the tail of the distribution of values of the test statistic for the 
random assignments. The percentile is the p-value of the null hypothesis.  
The primary test-statistic of interest for the first stage will be the difference in the medians 
between the treatment and control groups at Week 14. This statistic makes sense for ordinal 
variables such as the Likert scales that comprise each response. Other test statistics may also be 
investigated including:  
• The difference in treatment means at Week 14 
• The LS means from an ANCOVA at Week 14 with covariates for baseline value, site and 
sex 
• The LS means at Week 14 from an MMRM identical to the primary efficacy analysis 
In addition to performing the above analyses on the observed data, the randomization test will be 
repeated using multiple imputation implemented in a manner identical to that described for the 
primary analysis.  
 


 
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In a third analysis, the RHNP method will handle the missing data by assigning each subject with 
missing Week 14 values a +10 value for their change; since medians will be utilized, the 
particular value has no impact as long as it is larger than any possible change and less than 50% 
of the data are missing.  This amounts to assuming that missing responses are “bad” and should 
be scored as more extreme; the more data are missing, the more it will pull the median in the 
direction of a finding that treatment is ineffective. 
The performance characteristics of the RHNP method will be compared against the parametric 
approaches described for the primary analyses of the change from baseline to the Week 14 
endpoint in the diary NRS weekly average of daily self-reported average pain severity scores.  
  
10.4 Analyses by Dose 
Given that TNX-102 SL is generally well tolerated, it is unlikely that a large number of subjects 
will have a dose reduction to one tablet and hence it is nearly certain that an insufficient number 
will have such a reduction so as to allow the multiple imputation algorithm return stable results 
taking dose into account.   If more than 10 subjects in the active arm have a dose reduction at any 
point in the study, summary statistics on observed values for the primary and key secondary 
outcomes will be reported for placebo and each dose, with active treatment subjects grouped by 
whether they had a PI-directed dose reduction at any time point, regardless of the dose they were 
on at a particular time point.  Placebo subjects that had a “dose reduction” will not be grouped 
separately.  
 
 
 


 
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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 subject: 
• Adverse Events 
• Clinical Laboratory Investigations  
• C-SSRS 
• BDI-II 
• Vital Signs  
• Physical Examinations and examinations of the oral cavity 
11.1 Adverse Events 
All AEs, TEAEs, and SAEs will be coded using the MedDRA Dictionary Version 22.1. 
The collection of adverse events will begin at the time the subject 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, TEAEs by strongest relationship to study drug and 
post-treatment AEs. 
Each subject will be counted only once within each summation level (SOC; preferred term).  If a 
subject 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 


 
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from the date of randomization and a “no” response to the CRF question, “Did the AE start prior 
to the first dose?” 
11.1.1 Adverse Events Leading to Discontinuation of Study Drug  
A summary of incidence rates (frequencies and percentages) of TEAEs leading to 
discontinuation of study drug by treatment group, SOC, and preferred term will be prepared for 
the Safety population. 
A data listing of AEs leading to discontinuation of study drug will also be provided, displaying 
details of the event(s) captured on the CRF. 
11.1.2 Serious Adverse Events 
A summary of incidence rates (frequencies and percentages) of serious adverse events (SAE) by 
treatment group, SOC, and preferred term will be prepared for the Safety population.  A data 
listing of SAEs will also be provided, displaying details of the event(s) captured on the CRF. 
11.1.3 Oral TEAEs 
In light of the study drug’s sublingual route of delivery, subjects 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 subject, 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-subject 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 data (analytes for Chemistry and Hematology) 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.  ET data will be analyzed with the closest visit that does not have a valid assessment 
value. 
Laboratory values will be displayed in the data listings 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. 
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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. Frequency counts of yes/no responses to each item, and 
whether any suicidal ideation or behavior is present, will be summarized as described below. 
The overall number of subjects with lifetime and/or current suicidal ideation (by item and 
category), suicidal behavior (by item and category), or self-injurious non-suicidal behavior at the 
screening and baseline visit will be summarized by visit and treatment group.   
Additionally, the number of subjects with increase over baseline in suicidal ideation at any time 
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. 
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 
to act 
(4) Active suicidal ideation with any some intent to act, without 
specific plan 
(5) Active suicidal ideation with specific plan and intent 
B) Suicidal 
Behavior 
(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 subjects with suicidal ideation, suicidal 
behavior, or self-injurious behavior without suicidal intent at any visit.  For subjects 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. 


 
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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. 
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 the World Health Organization Drug Dictionary (WHO-DD 
Version 2019-Sep).  Prior and concomitant medications will be summarized by treatment group 
and by the number and percentage of subjects 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 subject 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 subjects’ 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- subject 
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 subjects’ diary data indicate dates that exceed this period, the diary dates will be 
utilized. 
Days of exposure will be based on subjects’ responses to the daily questions regarding 
medication usage.  The number of days on study drug is the total number of days a subject 
respond 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 subjects since 
they do not fill out a diary the day of their last visit).  The number of subjects 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 subject 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 subjects 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 subjects 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 
The protocol inadvertently omitted the in-clinic pain assessments from the list of exploratory 
endpoints; it was added to this SAP. 
 
 
 


 
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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. 
Carpenter, J. R. and Kenward, M. G. (2013), Multiple Imputation and Its Application, New 
York: John Wiley & Sons. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Scoring Guide. Available at 
http://cssrs.columbia.edu/scoring_cssrs.html 
Keller A, McGarvey EL, Clayton AH. Reliability and construct validity of the Changes in Sexual 
Functioning Questionnaire short-form (CSFQ-14). J Sex Marital Ther. 2006 ;32(1):43-52.  
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999;55(3):853-7 
Lehmacher, W., Wassmer, G. Adaptive sample size calculations in group sequential trials. 
Biometrics 1999;55: 1286-1290. 
Mehta C and Pocock S. Adaptive increase in sample size when interim results are promising: A 
practical guide with examples. Statistics in Medicine. 2010; 30: 3267–3284. 
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 Global Short Form. (2010, October 10). Scoring PROMIS Global short form. Retrieved 
from 
https://assessmentcenter.net/documents/Scoring%20PROMIS%20Global%20short%20form.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. 
TNX-CY-F304 IDMC Charter Final 13 Aug 2020 
TNX-CY-F304 ISAP Final 13 Aug 2020 
 
 


 
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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 
The following conventions will be used for calculation of a subject’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 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 
15.4 Appendix D 
The following list of numbers will be used for random seeds where required for MI processes: 
9179445 
2389546 
9954263 
5612645 
2599732 
7189411 
6986208 
6225777 
5483414 
8849556 
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, 
the second to last digit will be incremented by 1 to produce new seeds for the subsequent 
outcome.  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.  In no case will the same seed be used in 
more than one procedure; all seeds used will be documented in the programming specifications 
and the programs themselves. 
 


 
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15.5 Appendix E 
The following reporting conventions will be adopted for the presentation of study data.  These 
conventions will enhance the review process and help to standardize presentation with common 
notations. 
15.5.1 General Reporting Conventions 
• All tables and data listings will be developed in Landscape Orientation, unless 
presented as part of the text in a clinical study report (CSR). 
• Figures will be presented in Landscape Orientation, unless presented as part of the 
text in a CSR. 
• Legends will be used for all figures with more than one variable or item displayed. 
• Figures will be in black and white, unless color figures have been identified as useful 
for discriminating presentation in the figure.  Lines in figures should be wide enough 
to view the line after being photocopied. 
• Specialized text styles, such as bolding, italics, borders, shading, superscripted and 
subscripted text will not be used in tables, figures, and data listings unless they add 
significant value to the table, figure, or data listing.  
• Only standard keyboard characters should be used in tables and data listings. Special 
characters, such as non-printable control characters, printer specific, or font specific 
characters, will not be used on a table, figure, or data listing. Hexadecimal character 
representations are allowed (e.g., , , ). 
• All titles will be centered on a page. The ICH numbering convention is to be used for 
all tables, listings, and graphs (TLGs). 
• All footnotes will be left justified at the bottom of a page. Footnotes must be present 
on the page where they are first referenced. Footnotes should be used sparingly and 
must add value to the TLG. If more than four footnote lines are planned then a cover 
page may be used to display footnotes. 
• Missing values for both numeric and character variables will be presented as blanks 
in a table or data listing. A zero (0) may be used if appropriate to identify when the 
frequency of a variable is not observed. 
• All date values will be presented as YYYY-MM-DD (e.g., 2001-08-01) format. A 
four-digit year is preferred for all dates. 
• All observed time values will be presented using a 24-hour clock HH:MM:SS format 
(e.g., 01:35:45 or 11:26). Seconds should only be reported if they were measured as 
part of the study. 
• Time durations will be reported in mixed HHhr MMm SSs notation (e.g., 5h 32m, or 
27h 52m 31s). The use of decimal notation to present (display) time durations should 
be avoided (e.g. 0.083h = 5m) unless it is necessary to show the computation of time 


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