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

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).

Study Overview

• Status: Recruiting
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: NanoLithium® NP03; Drug: Placebo

Detailed Description

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
• Enrollment (Estimated): 68
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Solène GUILLIOT; Phone Number: +33 4 67 10 71 60; Email: solene.guilliot@medesispharma.com

Study Locations

• France
  • Lille, France, 59037
    • Recruiting
    • CHU de Lille
    • Contact: Thibaud LEBOUVIER, Dr; Phone Number: +33 3 20 44 54 93; Email: thibaud.lebouvier@chru-lille.fr
  • Limoges, France, 87042
    • Recruiting
    • CHU de Limoges - Hôpital Dupuytren
    • Contact: Achille TCHALLA, Prof.; Phone Number: +33 5 55 05 88 96; Email: achille.tchalla@chu-limoges.fr
  • Marseille, France, 13005
    • Recruiting
    • Hôpital de la Timone
    • Contact: Mathieu CECCALDI, Prof.; Phone Number: +33 4 91 38 64 20; Email: mathieu.ceccaldi@ap-hm.fr
  • Montpellier, France, 34295
    • Recruiting
    • CHU de Montpellier - Hôpital Gui de Chauliac
    • Contact: Karim BENNYS, Dr; Phone Number: +33 4 67 33 60 36; Email: k-bennys@chu-montpellier.fr
  • Paris, France, 75010
    • Recruiting
    • Hopital Lariboisiere
    • Contact: Claire PAQUET, Prof.; Phone Number: +33 1 40 05 43 39; Email: claire.paquet@aphp.fr
  • Strasbourg, France, 67000
    • Recruiting
    • Hôpital Universitaire de Strasbourg
    • Contact: Frédéric BLANC, Prof.; Phone Number: +33 3 88 11 58 58; Email: frederic.blanc@chru-strasbourg.fr
  • Toulouse, France, 31059
    • Recruiting
    • CHU Toulouse - Hôpital La Grave - Cité de la Santé
    • Contact: Maria SOTO MARTIN, Prof.; Phone Number: +33561776426; Email: soto-martin.me@chu-toulouse.fr
  • Villeurbanne, France, 69100
    • Recruiting
    • Hôpital des Charpennes - Hospices Civils de Lyon
    • Contact: Antoine GARNIER-CRUSSARD, Dr; Phone Number: +33 4 72 43 20 54; Email: antoine.garnier-crussard@chu-lyon.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NanoLithium® NP03; 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; 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.
Placebo Comparator: Placebo; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Medesis Pharma SA
• Investigators: Principal Investigator: Maria SOTO MARTIN, Prof., CHU Toulouse - Hôpital La Grave - Cité de la Santé

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2022
• Primary Completion (Actual): January 23, 2024
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: April 15, 2022
• First Submitted That Met QC Criteria: June 14, 2022
• First Posted (Actual): June 21, 2022

Study Record Updates

• Last Update Posted (Actual): April 12, 2024
• Last Update Submitted That Met QC Criteria: April 11, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: 2021 NanoLi-CT01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No