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

Medesis Pharma SA72 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Alzheimer's Disease

Interventions

NanoLithium® NP03DRUG

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.

PlaceboDRUG

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.

Eligibility

Sex: ALLMin age: 50 YearsMax age: 90 Years

Medical Language ↔ Plain English

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.

Locations (8)

CHU de Lille

Lille, France

CHU de Limoges - Hôpital Dupuytren

Limoges, France

Hôpital De La Timone

Marseille, France

CHU de Montpellier - Hôpital Gui de Chauliac

Montpellier, France

Outcomes

Primary Outcomes

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.

Time frame: 12 Weeks

Secondary Outcomes

Safety of treatment - Adverse effects

The number and types of adverse effects during the study and causal role of the study treatment.

Time frame: 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.

Time frame: 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)

Time frame: 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)

Time frame: 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)

Data from ClinicalTrials.gov

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Hôpital Lariboisière

Paris, France

Hôpital Universitaire de Strasbourg

Strasbourg, France

CHU Toulouse - Hôpital La Grave - Cité de la Santé

Toulouse, France

Hôpital des Charpennes - Hospices Civils de Lyon

Villeurbanne, France

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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 \[bpm\])

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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).

Time frame: 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).

Time frame: After 12 and 48 weeks

Efficacy of treatment_cognitive performances - MMSE Score

MMSE score (Units on a Scale).

Time frame: After 12 and 48 weeks

Efficacy of treatment_cognitive performances - CDRS Score

Clinical Dementia Rating Scale (CDRS) score (Units on a Scale).

Time frame: After 12 and 48 weeks

Efficacy of treatment_cognitive performances - ADL Score

Activity of Daily Living (ADL) score (Units on a Scale).

Time frame: After 12 and 48 weeks

Efficacy of treatment_PET-FDG

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

Time frame: After 12 and 48 weeks

Efficacy of treatment_Biomarkers_Peripheral biomarkers

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

Time frame: After 12 and 48 weeks

Efficacy of treatment_Biomarkers_Non-specific biomarkers

Non-specific biomarkers (inflammation cytokines).

Time frame: After 12 and 48 weeks

Efficacy of treatment_Drug compliance

Drug compliance by assessing the number of buccal deposits.

Time frame: After 12 and 48 weeks