A Double-Blind, Placebo-Controlled Safety and Efficacy Study of NA-831

Study Overview
=================
Brief Summary
-----------------
This study seeks to evaluate the efficacy and safety of NA-83 in subjects with mild cognitive impairment due to Alzheimer's Disease

Detailed Description
-----------------
Mild cognitive impairment (MCI) is defined as the symptomatic pre-dementia stage on the continuum of cognitive decline. Currently, no medications have proven effective for MCI. Preclinical experiments indicate that NA-831 is an endogenous small molecule that exhibits neuroprotection, neurogenesis, and cognitive protective properties across a range of disease models. NA-831 has been shown to be safe and well tolerated in healthy volunteers. This study seeks to evaluate the efficacy and safety of NA-83 in 126 subjects with mild cognitive impairment due to Alzheimer's Disease

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, and Efficacy of NA-831 in Alzheimer Patients With Mild Cognitive Impairment

Conditions
-----------------
Mild Cognitive Impairment, Alzheimer Disease, Alzheimer Dementia, Dementia, Vascular, Dementia With Lewy Bodies, Cognitive Impairment, Tauopathies, Neurodegenerative Diseases, Neurocognitive Disorders, Cognitive Disorder

Intervention / Treatment
-----------------
* Drug: N-831(Traneurocin) 10 mg QD
* Drug: NA-831 (Traneurocin) 20 mg QD
* Drug: NA-831 (Traneurocin) 40 mg QD
* Drug: Placebo oral capsule QD


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION Is male or female, at 55-85 years of age (inclusive) at screening self-reported memory complaint, corroborated by spouse or companion as appropriate. Wechsler Memory Scale III (WMS-III) age-adjusted Logical Memory II score ≤ 5. Mini-Mental State Exam (MMSE) ≥23 Center for Epidemiologic Studies-Depression (CES-D) score <27. Normal thyroid function, defined as TSH, T3 and T4 within normal limits. Agree not to consume alcoholic beverages within 8 hours of each study visit. Willing and able to sign informed consent and complete the CTB and all other tests and procedures as listed in the protocol. Able to read at a 6th grade level or equivalent Female subjects must be surgically sterile or post-menopausal for at least 2 years. If <2 years post-menopausal, then a follicle stimulating hormone (FSH) ≥40 mIU/mL must be obtained. If participant is receiving an acetylcholinesterase inhibitor or memantine, the dose must have been stable for at least three months before Screening Must have a reliable and competent trial partner/informant who has a close relationship with the participant and is willing to accompany the participant to all required trial visits, and to monitor compliance of the administration of the trial medication EXCLUSION CRITERIA Subjects who have any significant, untreated psychiatric illness or any CNS condition (such as schizophrenia, Parkinson's disease, stroke, etc.) that could interfere with the study evaluations or procedures or which poses an additional risk. Evidence of a clinically relevant or unstable psychiatric disorder, excluding major depression in remission History of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities. Have had a stroke or Transient Ischemic Attack (TIA) or unexplained loss of consciousness in the past 1 year History of seizures or epilepsy within the last 5 years History of hepatitis or liver disease that has been active within the 6 months prior toScreening History of malignancy occurring within the 5 years before Screening, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or localized prostate carcinoma Clinically significant vitamin B12 or folate deficiency in the 6 months before Screening History of unstable angina, myocardial infarction, chronic heart failure or clinically significant conduction abnormalities within 1 year prior to Screening Visit History of alcohol or substance abuse or dependence within the past year. Has human immunodeficiency virus (HIV) by medical history Acute infective sinusitis. History or presence of an abnormality of the external or internal structures of the nose or nasopharynx, except for surgical correction of the nasal septum or a broken nose at least 2 years previously, or surgical repair of cleft palate when <30 years of age. Use of medications that are known to cause frank obtundation of cognition History of or current significant systemic disease judged to interfere with the study evaluations or likely to be a safety concern. Untreated sleep apnea or treatment for sleep apnea for <3 months. Clinically significant systemic illness or serious infection within 30 days prior to or during the screening period Use of allowed medications for chronic conditions at doses that have not been stable for at least 4 weeks prior to Screening, or use of AD medications at doses that have not been stable for at least 8 weeks prior to Screening Abnormal clinical laboratory test results, specifically: Alanine transaminase (ALT) or aspartate transaminase (AST) >2 х the upper limit of normal (ULN),Hematology <80% the lower limit of normal, Creatinine ≥2 mg/dL and ,Other clinical laboratory values or vital signs considered clinically significant in the opinion of the Investigator. Treatment with any investigational drug, biologic, or device within the previous 30 days prior to screening. Surgery involving general anesthesia within the past 3 months or planned surgery requiring general anesthesia during the study period. Contraindications to study procedures Use of any medications that, in the opinion of the Investigator, may contribute to cognitive impairment, put the participants at higher risk for adverse events (AEs), or impair the participant's ability to perform cognitive testing or complete study procedures.

Ages Eligible for Study
-----------------
Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low-dose N-831(Traneurocin)- 10 mg QD<br>Oral administration of 10 mg of NA-831 (Traneurocin) per day for 24 weeks | Drug: N-831(Traneurocin) 10 mg QD<br>* Oral administration of 10 mg capsule of NA-831 QD for 24 weeks<br>|
| Experimental: Medium-dose NA-831(Traneurocin)- 20 mg QD<br>Oral administration of 20 mg of NA-831(Traneurocin) per day for 24 weeks | Drug: NA-831 (Traneurocin) 20 mg QD<br>* Oral administration of 20 mg capsule of NA-831 QD for 24 weeks<br>|
| Experimental: High-dose NA-831(Traneurocin)- 40 mg QD<br>Oral administration of 40 mg of NA-831(Traneurocin) per day for 24 weeks | Drug: NA-831 (Traneurocin) 40 mg QD<br>* Oral administration of 40 mg capsule of NA-831 QD or for 24 weeks<br>|
| Placebo Comparator: Placebo<br>Oral administration of placebo per day for 24 weeks | Drug: Placebo oral capsule QD<br>* Oral administration of oral placebo capsule QD or 24 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Clinical Dementia Rating Scale- Sum of Boxes (CDR-SB) score at Week 24 | To study to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score at Week 2 and Week 24. The CDR-SB is obtained through interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The CDR-SOB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18 with the higher values represent worse outcome. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. Mean difference between the last (Week 24) and first (Week 2) postdose using Clinical Dementia Rating Scale- Sum of Boxes (CDR-SB) assessment | To assess the Clinical Dementia Rating Scale- Sum of Boxes (CDR-SB) mean difference between the Week 2 and Week 24. The CDR-SB is obtained through interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The CDR-SOB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18, with the higher values represent worse outcome. | Week 24 | 
| Assess the change from baseline in ADCS-ADL MCI at Week 24 | Change from baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS-ADL MCI) at Week 24. The Galasko method for Alzheimer Disease Cooperative Study (ADCS) will be used, which contains 23 items covering physical and mental functioning and independence in self-care. For Activities of Daily Living (ADLs), the scoring used was the following: 0 = no impairment, 1 = problem performing but no supervision or assistance needed, 2 = problem requiring supervision, 3 = problem with assistance needed, and 4 = unable to perform. The scores range from 0 to 78, with higher values indicates greater disability. | Week 24 |