Clinical Safety and Efficacy Evaluation of NanoLithium® NP03 in Patients With Mild-to-severe Alzheimer's Disease

Prospective, Multicenter, First Part Randomized, Placebo-controlled, Parallel-group, Double-blind Period Followed by Open-label Trial Period to Evaluate Clinical Safety & Efficacy of NanoLithium® NP03 in Patients With Mild-to-severe Alzheimer's Disease: Proof-of-concept Study

This proof-of-concept study will assess safety, tolerance, and efficacy of NanoLithium® NP03 in patients with mild-to-severe Alzheimer's Disease (AD).

This French Study is a prospective, multicenter, randomized (1:1), placebo-controlled, parallel-group, double-blind period followed by an open-label trial period to Evaluate Clinical Safety and Efficacy of NanoLithium® NP03 in Patients With Mild-to-severe Alzheimer's Disease.

Patients will be randomized into two treatment arms:

• NanoLithium® NP03 (N=34)
• Placebo (N=34)

The first phase will consist of a double blind 12-week -period, which will be followed by an open-label 36-week period for each arm.

A total of 18 clinical or phone call visits are scheduled during this study. During the follow-up, clinical, biological, electrophysiological, imaging assessments and questionnaires will be performed to determine the safety, efficacy, and disease-modifying effect of NanoLithium® NP03.

Inclusion Criteria:

• Male and female patients between 50 and 90 years inclusive;
• Sufficient clinical and paraclinical information for the diagnosis of AD according to the international diagnosis criteria from McKhann G. M. et al. 2011;
• Patient presents clinically significant behavioral and psychological symptoms of dementia (BPSD) requiring medication in the opinion of the study physician (at least one item of the Neuropsychiatric Inventory-12 [NPI-12] with a score ≥ 4);
• Mild to-severe AD with a Minimal Mental State Examination (MMSE) score from 10 to 26 included;
• Symptomatic treatments of AD (acetylcholinesterase inhibitors and memantine) and psychotics drugs (benzodiazepines, antidepressants, anxiolytics, neuroleptics) are allowed but need to be maintained during at least 4 weeks before inclusion and during the follow-up;
• Female patient of childbearing potential must be willing to use an efficient birth control method during the study and until 5 days after the end of the treatment.

A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus, tubal ligation).

The following are acceptable contraceptive methods: - Established use of oral, injected, or implanted hormonal methods of contraception - Intrauterine system or placement of an intrauterine device - Double barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam, gel, film, cream, or suppository - True abstinence [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception]

• Male patient must be willing to use male contraception (condom) during the study;
• Patient must have availability of a person ("study partner" or caregiver) who has frequent and sufficient contact with the patient, can provide accurate information regarding the patient's behavior, cognitive, and functional abilities as well as his/her health throughout the study, and agrees to provide information at investigational site visits;
• Patient is willing and able to give informed consent. If the study patient is not competent, a legally authorized representative must provide informed consent on his/her behalf, and the patient must provide assent;
• Patient affiliated to French social security;
• Patient is willing to and can comply with the study protocol requirements, in the opinion of the investigator.
• If the patient took part to another therapeutic clinical trial, he/she must systematically observe a wash-out period of > 4 weeks, or of > 6 months if he/she received a biologic disease modifying treatment (antibodies targeting the β-amyloid protein or the p-Tau protein) or 5 half-lives of investigational drug(s), whichever is longer.

Exclusion Criteria:

• Patient with genetic form of AD (known genetic mutation);
• Patient with major physical or neurosensory problems likely to interfere with the tests; contraindication or refusal to perform functional brain imaging examinations;
• Absence of caregivers to complete psychological and behavioral scales and/or questionnaires;
• Patient with illiteracy and/or inability to perform psychological and behavioral evaluations;
• Pathologies involving short term vital prognosis (progressive cancer, unstable heart failure, severe liver, kidney or respiratory diseases);
• Primary chronic psychosis or psychotic episodes not associated with the AD pathology;
• Addiction to alcohol or drugs;
• Pregnancy or breast-feeding;
• Epilepsy or other neurodegenerative disorders;
• Vitamin B12 or folic acid deficiency without supplementation;
• Patient participating in another drug trial;
• Thyroid disorders not treated;
• Patient living in institution;
• Patient deprived of liberty by law;
• Patient with contraindications to drugs containing lithium: heart failure, renal failure, Addison disease, and Brugada syndrome.