Prevention/Reduction of ASRs and PTSD to Sustain Civilian Performance With Sublingual Cyclobenzaprine HCl (TNX-102 SL)

Phase 2

Not yet recruiting

• Conditions: Acute Stress Reaction; Acute Stress Disorder; Neurocognitive Function; Post-traumatic Stress
• Interventions: Drug: Cyclobenzaprine HCl; Drug: Placebo

• Registration Number: NCT06636786
• Lead Sponsor: University of North Carolina, Chapel Hill

Brief Summary

This study will examine the safety and efficacy of TNX-102 SL to reduce ASR symptoms and behavioral changes among patients presenting to the emergency department (ED) after motor vehicle collision (MVC). Specifically, the investigators will perform the Optimizing Acute Stress reaction Interventions with TNX-102 SL (OASIS) Trial, a double-blind placebo-controlled randomized clinical trial (RCT) to determine if TNX-102 SL initiated in the ED in the hours after MVC to high risk individuals, treats/reduces acute stress reaction (ASR)/acute stress disorder (ASD) symptoms (primary outcome), improves neurocognitive function, and prevents/reduces posttraumatic stress (PTS) symptoms (secondary outcomes) long term. 180 participants will be randomized, receive study drug in ED and be discharged with a 2-week drug supply. Prior to initial dose of study drug administration, and during the hours, days, and weeks after participants will receive serial longitudinal assessments of psychological and somatic symptoms, neurocognitive function, and adverse events.

Detailed Description

U.S. military personnel are exposed to life-threatening traumatic events (e.g., intense firefights with multiple casualties) that result in acute stress reaction (ASR) symptoms (ICD-10) and posttraumatic stress (PTS). Similarly, acute and persistent stress symptoms, and related adverse posttraumatic neuropsychiatric sequelae, are also very common and cause a tremendous burden of suffering in civilian populations following exposure to life-threatening traumatic events (e.g., motor vehicle collision, violent or accidental death of a loved one, and assault). TNX-102 SL (cyclobenzaprine HCl sublingual tablet) is being developed for the management of fibromyalgia (FM), and post-traumatic stress disorder (PTSD) by Tonix Pharmaceuticals, Inc; the FM program is in mid-Phase 3 development and PTSD is Phase 3 ready. In previous PTSD and fibromyalgia studies, TNX-102 SL has demonstrated the ability to improve sleep quality, which, based on published clinical studies of fear memory and stress responsiveness, has been shown to play a significant role in stress recovery. To date, TNX-102 SL has undergone an intense nonclinical and clinical development including Phase 1, 2, and 3 studies that assessed safety in over 1,180 subjects. TNX-102 SL is an extremely promising agent to reduce ASR symptoms and related behavioral changes, to enhance resilience and improve warfighter performance, and to reduce the frequency and severity of persistent/chronic PTS symptoms. The results of this study will ultimately provide military personnel, veterans, and civilians with an important new treatment option that, when administered in the early aftermath of traumatic stress exposure, can improve recovery, job performance, and quality of life.

Study Timeline

• Status Verified: 2024-08
• Study First Submitted: 2024-09-05
• Study First Submitted QC: 2024-10-08
• Study First Posted: 2024-10-15
• Last Update Submitted: 2024-12-04
• Last Update Posted: 2024-12-06
• Study Start: 2025-01
• Primary Completion: 2025-09
• Study Completion: 2025-09

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 180

Inclusion Criteria

• ≥ 18 years and ≤ 55 years of age
• Admitted to ED within 24 hours of MVC
• Anticipated to be discharged home from the ED
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Has a smartphone with continuous service for ≥ 1 year
• Has a personal email address they regularly access
• Able to speak and read English
• PTS prediction tool risk score ≥ 16 in the ED
• Pain severity in the ED ≥ 4 (0-10 numeric rating scale)
• People who are not of childbearing potential (e.g., hysterectomy, bilateral oophorectomy, or confirmed postmenopausal for at least last 12 consecutive months)
• People with the capacity to conceive a pregnancy must agree to employ a highly effective form of birth control throughout the first 21 days of study participation (e.g., oral, injected, transdermal, or implanted hormonal methods of contraception for at least one full menstrual cycle prior to study drug administration; placement of an intrauterine device (IUD) or intrauterine system (IUS); or double barrier methods such as condoms and diaphrams)

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Exclusion Criteria

• Substantial comorbid injury (e.g., long bone fracture)
• People of childbearing potential who are pregnant, breastfeeding, planning to become pregnant, or not using a highly effective form of contraception (e.g., implants, intrauterine devices (IUDs), tubal ligation, hormonal birth control pills, patches, vaginal rings, or injections) during their participation
• Prisoner status
• Chronic daily opioid use prior to MVC (>20 mg oral daily morphine equivalents)
• Active psychosis, suicidal ideation, or homicidal ideation
• Plans for hospital admission
• History of arrhythmias, heart block or conduction disturbances, congestive heart failure
• Currently in the acute recovery phase of myocardial infarction
• Known hypersensitivity to cyclobenzaprine or the excipient in TNX-102 SL or placebo formulations
• History of urinary retention, angle-closure glaucoma, increased intraocular pressure, or hyperthyroidism(known or identified in ED as Thyroid Stimulating Hormone (TSH) < lower limit of normal)
• Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation due to risk of potential fatal drug-drug interactions
• Current or planned use of the following prohibited concomitant medications during study participation: anticholinergic medications, guanethidine, selective serotonin reuptake inhibitors (SSRIs) , serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, MAO inhibitors, anticholinergic medications, guanethidine, potent cytochrome P450 subtype 3A4 inhibitor, St. John's wort, or other prohibited concomitant medications listed in section 5.6
• Any hepatic impairment or renal disease (defined as aspartate transaminase (AST) or alanine transaminase (ALT) > 3 times the upper limit of normal) or renal disease (defined as glomerular filtration rate (GFR) ≤ 80 mL/min)
• Lacking capacity to provide informed consent (receipt of sedative, hypnotic agent making the patient non-decisional for consent)
• Any other history or condition that would, in the site investigator's judgement, indicate that the patient would very likely be non-compliant with the study or unsuitable for the study (e.g., might interfere with the study, confound interpretation, or endanger patient)
• Elevated baseline blood pressure defined as systolic blood pressure ≥ 170 mmHg or diastolic blood pressure ≥ 100 mmHg
• Abnormal baseline ECG as defined as: QRS duration ≥ 120 ms; QTc > 460 ms; not in sinus rhythm; or 1st, 2nd, or 3rd degree heart block indicated
• Known substance or alcohol use disorder, bipolar disorder, or schizophrenia

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cyclobenzaprine HCl	Cyclobenzaprine HCl	Participants will be instructed to take a half dose (equivalent to 1 tablet, 2.8 mg) of placebo in the ED as part of enrollment procedures. If the time between the first half dose and the planned bedtime of the participant is less than 6 hours, participants will be instructed to take 1 tablet (half dose) the first night at bedtime. If the time between the first half dose and planned bedtime of the participant is greater than or equal to 6 hours, then participants will be instructed to take a full dose (equivalent to 2 tablets) the first night. Over the following 13 days, all participants will be instructed to take a full dose of the study drug at bedtime. Each participant will receive 29 tablets and take either 28 or 29 tablets total for the duration of study participation.
Placebo	Placebo	Participants will be instructed to take a half dose (equivalent to 1 tablet, 2.8 mg) of placebo in the ED as part of enrollment procedures. The placebo is the same formulation as active except the Cyclobenzaprine HCl content is replaced by Mannitol to maintain the same tablet weight and dimensions. If the time between the first half dose and the planned bedtime of the participant is less than 6 hours, participants will be instructed to take 1 tablet (half dose) the first night at bedtime. If the time between the first half dose and planned bedtime of the participant is greater than or equal to 6 hours, then participants will be instructed to take a full dose (equivalent to 2 tablets) the first night. Over the following 13 days, all participants will be instructed to take a full dose of the study drug at bedtime. Each participant will receive 29 tablets and take either 28 or 29 tablets total for the duration of study participation.

Primary Outcome Measures

Name	Time	Method
Change in ASD Score	Week 1, 3 after MVC	Individuals are asked to complete the 14-item Acute Stress Disorder Scale (ASDS) self-report inventory where each item is rated on a 5-point scale (0= Not at all; 1= Mildly; 2= Medium; 3= Quite a bit; 4= Very Much) that indexes acute stress disorder (ASD). Range of possible total scores is 0-56, with higher total scores indicating greater acute stress symptoms.

Secondary Outcome Measures

Name	Time	Method
Median reaction time of correct responses (general cognitive function)	Min 30, Hour 1, 6, 12, Day 1, 2, 3, Week 1, 2, 3, 5, 6, 8, 11, 12 after MVC	General cognitive function will be assessed using the Test My Brain Digit Symbol Matching Test. Participants will be asked to match symbols and numbers using a symbol-number key shown on screen. General cognitive function is assessed via measuring median reaction time of correct responses (medianRTc) to 'test' trials. Range for medianRTc (ms) is 0-30000.
Median reaction time of correct responses (procedural reaction time)	Min 30, Hour 1, 6, 12, Day 1, 2, 3, Week 1, 2, 3, 5, 6, 8, 11, 12 after MVC	Procedural reaction time will be assessed using the Test My Brain Choice Reaction Time Test. Participants see a set of three arrows, where one arrow is a different color from the rest. The participant presses left or right to indicate the direction of the odd colored arrow. Reaction time is assessed via measuring median reaction time of correct responses (medianRTc) to 'test' trials. Range for medianRTc (ms) is 0-5000.
Proportion of targets correctly identified (visuospatial processing and attention)	Min 30, Hour 1, 6, 12, Day 1, 2, 3, Week 1, 2, 3, 5, 6, 8, 11, 12 after MVC	Visuospatial processing and attention will be assessed using the Test My Brain Multiple Object Tracking Test. In this test of visuospatial processing and attention, participants have to track a set of target circles around the screen (amidst a field of distractors) that move at increasing speed with each trial. Once the circles stop moving, participants select which were targets must identify targets instead of distractors. Visuospatial processing and attention are assessed via the proportion of targets correctly identified. Range for measure is 0-1.
d-prime identification (psychomotor vigilance)	Min 30, Hour 1, 6, 12, Day 1, 2, 3, Week 1, 2, 3, 5, 6, 8, 11, 12 after MVC	Psychomotor vigilance will be assessed via the Test My Brain Gradual Onset Continuous Performance Test. In this task, participants monitor a stream of city and mountain images that rapidly fade from one to the next with no interstimulus interval. Participants are asked to press/touch for each city image and to withhold for each mountain image. Vigilance is assessed via measuring d-prime for identification of each city image, a signal detection-based measure that takes into account both hits and false alarms to provide an unbiased estimate of performance where higher values reflect better performance. Response inhibition is defined as the suppression of actions that are inappropriate in a given context. Response inhibition is assessed using results from the above, by measuring the number of commission errors (failure to withhold responses) where most positive scores reflect more impulsive responding. Range for measure is -4.2279 - 4.2279.
Change in Pain Symptom Score	Baseline, Week 1, 3, 6, 12 after MVC	The Regional Pain Scale (RPS) will be used to assess the extent of body pain. 13 items will be scored on a 0-10 pain scale where 0 is no pain and 10 is severe pain. Range of possible total scores is 0-130, with higher total scores indicative of greater pain symptoms
Change in Depressive Symptoms Score	Baseline, Week 1, 3, 6, 12 after MVC	The Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Short Form 8b; an 8-item scale, and one question from the PROMIS Depression Item Bank will be aggregated/combined to assess depression. Each item is scored on a 5-point scale where 0 is "none of the time" and 5 means "all or almost all of the time". Range of possible total scores is 0-45, with higher total scores indicative of greater depressive symptoms.
Change in Somatic Symptom Score	Baseline, Week 1, 3, 6, 12 after MVC	The Pennebaker Inventory of Limbic Languidness (PILL) assesses the frequency of common physical symptoms and sensations. We will use a version with adapted response options for greater consistency across measures, greater precision in response levels, and to allow administration via self-report. 20 items will be scored on a 0-10 scale where 0 is "no problem" and 10 means "major problem". Range of possible total scores is 0-200, with higher total scores indicative of greater somatic symptoms.
Change in PTSD Symptoms	Baseline, Week 1, 3, 6, 12 after MVC	The PTSD Checklist for DSM-5 (PCL-5) assesses PTSD symptoms as defined by the Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5). 20 items will be scored on a five-point scale ranging from 0 ("not at all") to 4 ("extremely"). Range of possible total scores is 0-80, with higher total scores indicative of greater PTSD symptoms.

Trial Locations

Locations (6)

Indiana University; 🇺🇸 Indianapolis, Indiana, United States

University of Massachusetts Chan Medical School (Umass Memorial Medical Center); 🇺🇸 Worcester, Massachusetts, United States

University of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States

Washington University in St. Louis; 🇺🇸 Saint Louis, Missouri, United States

Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States

The Miriam Hospital; 🇺🇸 Providence, Rhode Island, United States