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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: NanoLithium® NP03
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NanoLithium® NP03<br>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). | Drug: NanoLithium® NP03<br>* 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.<br>|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NPI-12 total score | 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. | 12 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of treatment - Adverse effects | The number and types of adverse effects during the study and causal role of the study treatment. | approximately 1 year | 
| Safety of treatment - Clinical assessments - associated pathologies | 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. | approximately 1 year | 
| Safety of treatment - Clinical assessments - biochemistry - AST/ALT | 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) | approximately 1 year | 
| Safety of treatment - Clinical assessments - biochemistry - Creatinine | 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) | approximately 1 year | 
| Safety of treatment - Clinical assessments - biochemistry - Glomerular filtration rate | 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) | approximately 1 year | 
| Safety of treatment - Clinical assessments - biochemistry - B9 vitamin | 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) | approximately 1 year | 
| Safety of treatment - Clinical assessments - biochemistry - B12 vitamin | 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) | approximately 1 year | 
| Safety of treatment - Clinical assessments - biochemistry - T3 | 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) | approximately 1 year | 
| Safety of treatment - Clinical assessments - biochemistry - T4 | 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) | approximately 1 year | 
| Safety of treatment - Clinical assessments - biochemistry - TSH | 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) | approximately 1 year | 
| Safety of treatment - Clinical assessments - Hematology | To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common biological tests assessment: Clinical laboratory evaluations: hematology | approximately 1 year | 
| Safety of treatment - Clinical assessments - Lithium blood level | To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common biological tests assessment: Clinical laboratory evaluations: lithium blood level | approximately 1 year | 
| Safety of treatment - Clinical assessments - Systolic and diastolic blood pressure | 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) | approximately 1 year | 
| Safety of treatment - Clinical assessments - Pulse rate | 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]) | approximately 1 year | 
| Safety of treatment - Clinical assessments - ECG - PR | To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: Electrocardiogram (ECG): PR interval (msec) | approximately 1 year | 
| Safety of treatment - Clinical assessments - ECG - QRS | To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: Electrocardiogram (ECG): QRS interval (msec) | approximately 1 year | 
| Safety of treatment - Clinical assessments - ECG - QT | To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: Electrocardiogram (ECG): QT interval (msec) | approximately 1 year | 
| Safety of treatment - Clinical assessments - ECG - RR | To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: Electrocardiogram (ECG): RR interval (msec) | approximately 1 year | 
| Safety of treatment - Clinical assessments - ECG - QTcB | To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: Electrocardiogram (ECG): QTcB interval (msec) | approximately 1 year | 
| Safety of treatment - Clinical assessments - Weight | To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: General clinical examination: weight (in Kg) | approximately 1 year | 
| Safety of treatment - Clinical assessments - Height | To assess the safety of NanoLithium® NP03 after 48 weeks of treatment based on common clinical assessment: General clinical examination: height (in cm) | approximately 1 year | 
| Safety of treatment - Clinical assessments - BMI | 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) | approximately 1 year | 
| Safety of treatment - Clinical assessments - cognitive signs | 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 | approximately 1 year | 
| Safety of treatment - Clinical assessments - focal neurological signs | 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 | approximately 1 year | 
| Safety of treatment - Clinical assessments - motricity | 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 | approximately 1 year | 
| Efficacy of treatment_BPSD_NPI-C-IPA | 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). | After 12 and 48 weeks | 
| Efficacy of treatment_BPSD_NPI-12 | To assess the BPSD at 12 and 48 weeks, score of each item of the Neuropsychiatric Inventory (NPI-12) (Units on a Scale). | After 12 and 48 weeks | 
| Efficacy of treatment_cognitive performances - MMSE Score | MMSE score (Units on a Scale). | After 12 and 48 weeks | 
| Efficacy of treatment_cognitive performances - CDRS Score | Clinical Dementia Rating Scale (CDRS) score (Units on a Scale). | After 12 and 48 weeks | 
| Efficacy of treatment_cognitive performances - ADL Score | Activity of Daily Living (ADL) score (Units on a Scale). | After 12 and 48 weeks | 
| Efficacy of treatment_PET-FDG | Cerebral metabolic rate for glucose measured by Positron Emission Tomography-Fluorodeoxyglucose (PET-FDG). | After 12 and 48 weeks | 
| Efficacy of treatment_Biomarkers_Peripheral biomarkers | Pathophysiological peripheral biomarkers (amyloid biomarkers, neurofilaments, Tau protein, BDNF) (pg/ml). | After 12 and 48 weeks | 
| Efficacy of treatment_Biomarkers_Non-specific biomarkers | Non-specific biomarkers (inflammation cytokines). | After 12 and 48 weeks | 
| Efficacy of treatment_Drug compliance | Drug compliance by assessing the number of buccal deposits. | After 12 and 48 weeks |