A Safety and Efficacy Study of NNZ-2566 in Patients With Mild Traumatic Brain Injury (mTBI)

A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of NNZ-2566 in the Acute Treatment of Adolescents and Adults With Mild Traumatic Brain Injury (mTBI)

The purpose of this study is to determine whether NNZ-2566 is safe and well tolerated in the treatment of mTBI in adolescents and adults.

Traumatic brain injury (TBI) is an injury to the head caused by an external trauma that can lead to brain cell death, inflammation, edema, hemorrhage, and disruption of normal brain cell function. mTBI frequently results in persistent functional impairment including problems with cognitive function, memory, mood, and other personality disorders.

There are currently no drugs available to reduce the brain damage or sequelae that result from TBI. Clearly, a safe and effective treatment for concussion injury and all forms of TBI would be an important development for military personnel as well as the general population.

This study will investigate the safety and tolerability of treatment with oral administration of NNZ-2566 at 35 mg/kg or 70 mg/kg BID in adolescents and adults with mTBI. The study also will also investigate measures of efficacy during treatment.

Inclusion Criteria:

1. Subject has a diagnosis of mTBI resulting from an injury that meets the following criteria:

   1. Occurred within 24 hours of Screening and was associated with a clear mechanism of injury and an alteration of consciousness (e.g., confusion, feeling dazed, or "seeing stars")
   2. Was associated with a GCS score of 13-15
   3. Was associated with 1 or more of the following signs and symptoms, as determined by a qualified clinician:

   i. Headache ii. Loss of consciousness iii. Post traumatic amnesia iv. Retrograde amnesia v. Difficulty concentrating vi. Balance problems vii. Dizziness viii. Visual problems ix. Personality changes x. Fatigue xi. Sensitivity to light/noise xii. Numbness xiii. Nausea xiv. Vomiting d. Current symptoms associated with the mTBI are causing clinically significant impairment

2. Subject is 16 to 55 years old.

3. Subject has a CGI-S score of ≥3 at Screening

4. Subject has an RPQ-3 score of ≥3 at Screening

5. Subjects who are taking psychotropic medications must have been receiving a stable regimen (i.e., same dosage and regimen) for at least 4 weeks prior to Screening. For the purposes of this protocol, psychotropic medications are defined as medications that are prescribed for intended CNS benefits. Medications for headache are permissible, as needed, according to approved prescribing information.

6. Women of child-bearing potential must have a negative urine pregnancy test at Screening. Men and women must agree to use a contraceptive method with <1% success rate (e.g., oral contraceptive, injectable progestogen, levonorgestrel implant, estrogenic vaginal ring, percutaneous contraceptive patch, intrauterine device [IUD], surgical sterilization, or double barrier method [i.e., condom with diaphragm or spermicidal agent]).

Exclusion Criteria:

Subjects are ineligible for the study if they meet any of the following exclusion criteria:

1. Subject has a history of brain surgery or prior severe TBI (based on a previously documented GCS score of ≤8).
2. Subject has a history of seizure disorder or has experienced seizures in the 24 hours preceding Screening. Note: Isolated febrile seizures during early childhood are not exclusionary.
3. Subject has a history of diabetes mellitus requiring pharmacotherapy within the preceding 12 months.
4. Subject has a history of hypothyroidism within the 3 years preceding Screening that currently requires or did require pharmacotherapy.
5. Subject has regularly used more than 1 of the following psychoactive medications in the 4 weeks preceding Screening: methylphenidate, dextroamphetamine, mixed amphetamine salts, amantadine, memantine, cholinesterase inhibitors, modafinil, or armodafinil.
6. Subject has a history of substance abuse or dependence, other than nicotine dependence, within the 3 months preceding Screening.
7. Subject has signs/symptoms of acute impairment due to alcohol use.
8. Subject has used anti-epileptic medications in the 4 weeks preceding Screening.
9. Subject has used bromocryptine, levodopa, ropinirole, or pramipexole in the 4 weeks preceding Screening.
10. Subject has a history of a major psychiatric disorder (including major depression, a clinically significant anxiety disorder, or a psychotic disorder) that is associated with significant clinical impairment within the preceding 6 months.
11. In the Investigator's opinion, the subject poses a current homicidal or serious suicidal risk, and/or has made a suicide attempt within the 6 months preceding Screening.
12. Subject has a neurological disorder other than mTBI (e.g., Parkinson's disease, stroke, multiple sclerosis, dementia, delirium, infectious encephalopathy) that has required treatment within the 6 months preceding Screening.
13. Subject has a history of, or current, cerebrovascular disease.
14. Subject has a history of, or current, malignancy.
15. Subject has an unstable medical disorder that may pose a safety concern or interfere with the accurate assessment of safety or efficacy.
16. Subject has laboratory values at Screening deemed to be clinically significant by the Investigator.
17. Subject has an average QT interval corrected using Fridericia's formula (QTcF) >450 msec at Screening or any ECG abnormality that may pose a potential safety concern.
18. Subject has a history of risk factors for torsade de pointes (e.g., heart failure, clinically significant hypokalemia, a serum potassium value at Screening of <3.0 mmol/L, or a family history of long QT syndrome).
19. Subject has a history of QT/QTcF prolongation previously or currently controlled with medication, in which normal QT/QTcF intervals could or can only be achieved with medication.
20. Subject has participated in another clinical treatment study within the 4 weeks preceding Screening.
21. Subject is unable to provide informed consent (where deemed cognitively able by standard assessments) or informed consent cannot be obtained from a legally authorized individual (e.g., spouse, or in the instance of minors, a parent).
22. Subject is pregnant or nursing.
23. Subject was previously enrolled in this study.
24. Subject has an allergy to strawberries.