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

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.

A prospective, multicenter, with a first randomized, placebo-controlled, parallel-group, double-blind period followed by an open-label trial period to evaluate the clinical safety and efficacy of NanoLithium® NP03 in patients with mild-to-severe Alzheimer's disease: a proof-of-concept study.

Double-blind period followed by an open-label trial period. The double-blind will be maintained throughout the double-blind period treatment (except exceptional unblinding in emergency situations for reasons of patient safety).

Description: Homogeneous yellow oily liquid. Dosage: One administration of 3 mL per day (1.8 mg/day) by depositing 1.5 mL in the gingivo-jugal groove of each cheek with the graduated pipette. Duration of treatment: Approximately one year (12 weeks for the double-blind period and 36 weeks for the subsequent open-label period).

Description: Homogeneous yellow oily liquid. Dosage: One administration of 3 mL per day (1.8 mg/day) by depositing 1.5 mL in the gingivo-jugal groove of each cheek with the graduated pipette. Duration of treatment: 12 weeks during the double-blind period.

One administration of 3 mL per day (1.8 mg/day) by depositing 1.5 mL in the gingivo-jugal groove of each cheek with the graduated pipette.

One administration of 3 mL per day (1.8 mg/day) by depositing 1.5 mL in the gingivo-jugal groove of each cheek with the graduated pipette.

The change from baseline to end of double-blind period (W12) of the NPI-12 total score in the NanoLithium® NP03 arm and in the placebo arm.

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: associated pathologies: medical conditions start and end date or ongoing, currently treated or not, recorded from patients file.

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common biological tests assessment: Clinical laboratory evaluations: biochemistry: AST/ALT (UI/L)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common biological tests assessment: Clinical laboratory evaluations: biochemistry: Creatinine (mg/L or µmol/L)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common biological tests assessment: Clinical laboratory evaluations: biochemistry: Glomerular filtration rate -Cockcroft or MDRD method - (ml/min/1,73m2)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common biological tests assessment: Clinical laboratory evaluations: biochemistry: B9 vitamin (µg/L or nmol/L)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common biological tests assessment: Clinical laboratory evaluations: biochemistry: B12 vitamin (ng/L or pmol/L)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common biological tests assessment: Clinical laboratory evaluations: biochemistry: T3 (µg/L or nmol/L)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common biological tests assessment: Clinical laboratory evaluations: biochemistry: T4 (µg/L or nmol/L)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common biological tests assessment: Clinical laboratory evaluations: biochemistry: TSH (mlU/L)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common biological tests assessment: Clinical laboratory evaluations: hematology

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common biological tests assessment: Clinical laboratory evaluations: lithium blood level

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: Vital signs: Systolic and diastolic blood pressure (mm Hg)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: Vital signs: Pulse rate (beats per minute [bpm])

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: Electrocardiogram (ECG): PR interval (msec)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: Electrocardiogram (ECG): QRS interval (msec)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: Electrocardiogram (ECG): QT interval (msec)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: Electrocardiogram (ECG): RR interval (msec)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: Electrocardiogram (ECG): QTcB interval (msec)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: General clinical examination: weight (in Kg)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: General clinical examination: height (in cm)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: General clinical examination: body mass index (BMI) (weight and height will be combined to report BMI in kg/m^2)

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common neurological assessments: Neurological clinical examination: cognitive signs: questions asked to patients/caregiver to detect execution troubles, attention troubles, language, gnosic troubles, praxis, visuo-spacial troubles and temporo-spacial orientation

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common neurological assessments: Neurological clinical examination: focal neurological signs: questions asked to patients/caregiver to detect extrapyramidal syndrome, pyramidal syndrome, cerebellar syndrome, frontal syndrome, hallucinations, dysautonomia, sensitive system and epilepsy

To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common neurological assessments: Neurological clinical examination: motricity: questions asked to patients/caregiver to detect muscular tonus, abnormal movements, reflex, walking troubles, falls, postural troubles, coordination, sphincter and trophic troubles

To assess the BPSD at 12 and 48 weeks, change from baseline to week 12 and week 48 on the Neuropsychiatric Inventory - Clinician items mapped to International Psychogeriatric Association (NPI-C-IPA) scale (Units on a Scale).

To assess the BPSD at 12 and 48 weeks, score of each item of the Neuropsychiatric Inventory (NPI-12) (Units on a Scale).

Cerebral metabolic rate for glucose measured by Positron Emission Tomography-Fluorodeoxyglucose (PET-FDG).

Pathophysiological peripheral biomarkers (amyloid biomarkers, neurofilaments, Tau protein, BDNF) (pg/ml).

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.