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

University of North Carolina (UNC)

Status and phase: Enrolling; Phase 2

Conditions: Acute Stress Disorder; Neurocognitive Function; Post-traumatic Stress; Acute Stress Reaction

Treatments: Drug: Placebo; Drug: Cyclobenzaprine HCl

Study type: Interventional

Funder types: Other; Other U.S. Federal agency; Industry

Identifiers

NCT06636786

23-0711

Details and patient eligibility

About

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.

Full 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.

Enrollment: 180 estimated patients

Sex: All

Ages: 18 to 55 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. ≥ 18 years and ≤ 55 years of age
2. Presentation to ED and able to complete enrollment visit activities within 72 hours of MVC
3. Anticipated to be discharged home from the ED
4. Stated willingness to comply with all study procedures and availability for the duration of the study
5. Consent to receive unencrypted communications
6. Has a smartphone with continuous service for ≥ 1 year
7. Has a personal email address they regularly access
8. Able to speak and read English
9. Pain severity in the ED ≥ 4 (0-10 numeric rating scale)
10. People who are not of childbearing potential (e.g., hysterectomy, bilateral oophorectomy, or confirmed postmenopausal for at least last 12 consecutive months)
11. People with the capacity to conceive a pregnancy must agree to employ a highly effective form of birth control throughout the first 28 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 diaphragms)

Exclusion criteria

1. Substantial comorbid injury (e.g., long bone fracture)

2. 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

3. Prisoner status

4. Any chronic daily opioid use prior to MVC

5. Active psychosis, suicidal ideation, or homicidal ideation

6. Plans for hospital admission

7. History of arrhythmias, heart block or conduction disturbances, congestive heart failure

8. Currently in the acute recovery phase of myocardial infarction

9. Hypersensitivity to cyclobenzaprine or the excipient in TNX-102 SL or placebo formulations

10. History of urinary retention, angle-closure glaucoma, increased intraocular pressure, or hyperthyroidism (TSH < lower limit of normal)

11. Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation due to risk of potential fatal drug-drug interactions

12. 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, chronic use muscle relaxants or planned use after MCV or other prohibited concomitant medications listed in section 5.6. PI to assess individual cases where single dose of muscle relaxant is prescribed in ED for inclusion

13. Any hepatic impairment or renal disease (defined as AST OR ALT > 3 times the upper limit of normal) or renal disease (defined as GFR ≤ 80 mL/min)

14. In addition to the lab results in exclusion #13 above, exclude patients who report the following and or if the following are in medical records -

    • history of renal disease
    • history of urinary retention, angle-closure glaucoma, increased intraocular pressure, or hyperthyroidism

15. As part of additional screening, exclude patients who answer yes to any of the questions listed below-

    • Have you ever been told that you have renal or kidney disease?
    • Have you ever been diagnosed with hyperthyroidism or active overactive thyroid?
    • Have ever been told that you have a liver disease or cirrhosis, or problems with your liver?

16. Any history of seizure disorder

17. Lacking capacity to provide informed consent (receipt of sedative, hypnotic agent making the patient non-decisional for consent)

18. 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)

19. Elevated baseline blood pressure defined as systolic blood pressure ≥ 170 mmHg or diastolic blood pressure ≥ 100 mmHg and or elevated heart rate of ≥115

20. 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

21. Substance or alcohol use disorder, bipolar disorder, or schizophrenia

22. History of severe or unexplained oral, or oropharyngeal swelling or edema

23. History of presyncope or syncopal episodes

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

---

180 participants in 2 patient groups, including a placebo group

Cyclobenzaprine HCl

Experimental group

Description:

Participants will be instructed to take a half dose (equivalent to 1 tablet, 2.8 mg) of Cyclobenzaprine HCl 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.

Treatment:

Drug: Cyclobenzaprine HCl

Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo