Efficacy and Safety of Dimethyl Fumarate Among Patients with Mild Cognitive Impairment and Dementia Due to Alzheimer's Disease

Randomized, Double-blind, Placebo- Controlled Trial Evaluating Efficacy and Safety of Dimethyl Fumarate in Brain Atrophy Reduction, Synaptic Functional Connectivity, Cognitive Functions, Quality of Life, and Activity of Daily Living Improvement Among Patients with Mild Cognitive Impairment and Dementia Due to Alzheimer's Disease

The goal of this clinical trial is to assess the degree of improvement in cognitive functions, including memory, attention, thinking, executive and language functions in diagnosed patients MCI and AD taking dimethyl fumarate 480 mg daily compared to patients taking placebo. Participant will be 55 to 90 years old, both genders. The main question it aims to answer is: Changing the degree of cognitive improvement based on the RBANS score among patients diagnosed with MCI and AD after completing dimethyl fumarate therapy test group compared to the placebo group.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer's Disease; MCI; MCI-AD, Early Stage Alzheimer's Disease
• Intervention / Treatment: Drug: dimethyl fumarate

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Medical University of Lodz Medical University of Lodz; Phone Number: +48 422725239; Email: cwbk@umed.lodz.pl
• Study Contact Backup: Name: Jakub Kazmierski, PhD; Phone Number: +48 426757372; Email: jakub.kazmierski@umed.lodz.pl

Study Locations

• Poland
  • Łódź, Poland, 92-213
    • Recruiting
    • Department of Old Age Psychiatry and Psychotic Disorders Medical University of Lodz
    • Contact: Jakub Kaźmierski

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Men and women aged 55-90 years.
2. Patients diagnosed with mild cognitive impairment in Alzheimer's disease and mild to moderate Alzheimer's dementia (MMSE >16) diagnosed based on NIA-AA criteria.
3. MMSE score from 17 to 30 points.
4. CDR score from 0.5 to 2.
5. The patient signs an informed, voluntary consent to participate in the study.
6. The patient has a close person/de facto guardian who agrees to help the patient during participation in the study.
7. At least 6 years of education.
8. In the case of anti-Alzheimer's drugs, the use of cholinesterase inhibitors is permitted provided that they are included at least 3 months before entering the study and used at a stable dose for at least 60 days before entering the study. In the case of memantine, its use is permitted provided that it is included at least 4 months before entering the study and used at a stable dose for at least 3 months before entering the study.

Exclusion Criteria:

1. Lack of informed voluntary consent to participate in the study.
2. Patients who cannot read or write.
3. Pregnant, breastfeeding or childbearing women who do not use effective contraception (hormonal contraception, surgical sterilization, intrauterine device, condom in combination with vaginal spermicide).
4. Participation in another clinical trial, currently or within 3 months prior to the screening visit.
5. Liver failure (i.e. cirrhosis or active liver disease), diagnosed acute or chronic hepatitis regardless of cause.
6. Chronic kidney disease with GFR below < 60 ml/min/m2
7. Abnormal liver parameters: ALAT exceeding > 2 times the upper limit of normal
8. Leukopenia (<4000/mm3), granulocytopenia (<1500/mm3) or lymphopenia (<1000/mm3) regardless of the cause.
9. Severe agitation.
10. Mental retardation.
11. Delirium diagnosed according to DSM-5 criteria.
12. Diagnosis of neurological and neurodegenerative diseases other than Alzheimer's disease (multiple sclerosis, Parkinson's disease, Huntington's disease, previous stroke).
13. Presence of hemorrhagic foci in magnetic resonance imaging with a diameter of ≥ 2 cm3, more than three (3) ischemic stroke foci with a diameter of ≥ 1.5 cm3 or a single ischemic foci with a diameter of ≥ 2 cm3, presence of vascular malformations, aneurysms, subdural hematoma, normal pressure hydrocephalus, final decision at the discretion of the investigator.
14. Severe or uncontrolled somatic disease that could affect the course of the study (e.g. neoplastic, cardiovascular, respiratory, metabolic or digestive, severe renal failure, unstable type I or II diabetes, untreated or uncontrolled clinically significant hypertension).
15. Use of benzodiazepines or barbiturates within 1 week prior to screening.
16. Pharmacological immunosuppression.
17. Patients with bipolar disorder or psychotic disorders or any other psychiatric condition (current or past) that the Investigator believes interferes with the study.
18. Alcoholism or drug addiction as defined by DSM-5 within the past 5 years (dependent for more than 1 year and or in remission for less than 3 years).
19. Patients with any medical condition that, in the Investigator's judgment, is an exclusion criterion.
20. Thyroid hormone therapy initiated, discontinued, or modified within 3 months prior to screening visit.
21. Menopausal hormone replacement therapy initiated, discontinued, or modified within 3 months prior to screening visit.
22. Use of prohibited drugs in the study: Antineoplastic drugs (no studies). Immunosuppressive drugs (no studies). Corticosteroids (impact on project results). Live attenuated vaccines (no studies). Inactivated vaccines may be used. Benzodiazepines (impact on assessed endpoints). Other ethyl esters used orally or topically.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Assessment of the degree of improvement in cognitive functions in diagnosed patients MCI and AD.; Assessment of the degree of improvement in cognitive functions, including memory, attention, thinking, executive and language functions in diagnosed patients MCI and AD taking dimethyl fumarate 480 mg daily compared to patients taking placebo.	Drug: dimethyl fumarate; 480 mg per day
Other: Assessment of the safety of therapy	Drug: dimethyl fumarate; 480 mg per day
Placebo Comparator: Assessment of the impact of therapy on patients' daily functioning; Assessment of the impact of therapy on patients' daily functioning - Scale Alzheimer's Disease Cooperative Study - Activity of Daily Living (ADCS-ADL).	Drug: dimethyl fumarate; 480 mg per day
Placebo Comparator: Assessment of the impact of therapy on the presence of symptoms neuropsychiatric/behavioral disorder; Assessment of the impact of therapy on the presence of symptoms neuropsychiatric/behavioral disorders in patients scale Neuropsychiatric Inventory (NPI), Geriatric Depression Scale (GDS).	Drug: dimethyl fumarate; 480 mg per day
Placebo Comparator: Assessment of the impact of therapy on the quality of life of patients and their caregivers; Assessment of the impact of therapy on the quality of life of patients and their caregivers (scales EQ-5D; Zarit Burden Interview).
Placebo Comparator: reducing the degree of brain atrophy in patients - MRI examination; Assessment of the impact of therapy on reducing the degree of brain atrophy in patients from the active group compared to the control group (MRI examination)	Drug: dimethyl fumarate; 480 mg per day
Placebo Comparator: impact of therapy on improvement in functional connections assessed in rs-fMRI rs-EEG; Assessment of the impact of therapy on improvement in functional connections assessed in rs-fMRI and rs-EEG	Drug: dimethyl fumarate; 480 mg per day
Placebo Comparator: Effect of therapy on peripheral markers of oxidative stress and pro-inflammatory markers; Assessment of the effect of therapy on peripheral markers of oxidative stress and pro-inflammatory markers	Drug: dimethyl fumarate; 480 mg per day
Placebo Comparator: degree of reduction in the rate of progression from MCI to dementia after completion; Assesment of the degree of reduction in the rate of progression from MCI to dementia after completion of the clinical phase of the study	Drug: dimethyl fumarate; 480 mg per day
Placebo Comparator: degree of improvement in cognitive functions using the MMSE and CDR scales; Assessment of the degree of improvement in cognitive functions using the MMSE and CDR scales	Drug: dimethyl fumarate; 480 mg per day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the degree of cognitive improvement based on the RBANS score among patients diagnosed with MCI and AD after completing dimethyl fumarate therapy test group compared to the placebo group.	The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a neuropsychological measure used in the assessment of cognitive function in older adults, studies of mild cognitive impairment and Alzheimer's disease dementia, and studies evaluating the effectiveness of therapeutic interventions. The test generates index scores in five neurocognitive domains, as well as a Total Scale Index score. The RBANS is characterized by high sensitivity in detecting disease and assessing changes in scores during treatment in patients with MCI in the course of Alzheimer's disease. with MCI and AD after completing dimethyl fumarate therapy test group compared to the placebo group.	15 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of the safety of therapy		15 months
Assessment of the impact of therapy on the daily functioning of patients - Alzheimer's Disease Cooperative Study - Activity of Daily Living (ADCS-ADL) scale.		15 months
Assessment of the impact of therapy on the presence of neuropsychiatric symptoms/behavioral disorders in patients using the Neuropsychiatric Inventory (NPI) scale and the Geriatric Depression Scale (GDS).		15 months
Assessment of the impact of therapy on the quality of life of patients and their caregivers (EQ-5D scales; Zarit Burden Interview).		12 months
Assessment of the effect of therapy on the reduction of the degree of brain atrophy in patients from the active group compared to the control group (MRI study).		6 months
Assessment of the effect of therapy on the improvement of functional connections assessed in rs-fMRI and rs-EEG.	EEG and MRI data will be processed using standard processing pipelines. The results will be a topographic map of the EEG frequency band distribution on the brain surface, temporal and time-frequency analyses based on FFT and wavelets, entropy analysis, and EEG coherence markers. Then, inverse localization of EEG signals generated on the scalp over the brain surface will be performed. Particular emphasis will be put on frontal structures and areas detected by MRI clustering. We will perform machine learning-based clustering of EEG and MRI data to detect significant features. CDR "Clinical Dementia Rating Assessment" score from 0.5 to 2	15 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of the effect of therapy on peripheral markers of oxidative stress and pro-inflammatory markers.		6 months
Assessment of the degree of reduction of the MCI progression rate to dementia after the end of the clinical phase of the study.		12 months
Assessment of the degree of improvement of cognitive functions using the MMSE and CDR scales.	MMSE (Mini-Mental State Examination) score from 17 to 30 points CDR (The Clinical Dementia Rating) score from 0,5 to 2 points	15 months

Collaborators and Investigators

• Sponsor: Medical University of Lodz

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: December 9, 2024
• First Submitted That Met QC Criteria: February 24, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 24, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Tauopathies; Neurodegenerative Diseases; Cognitive Dysfunction; Alzheimer Disease; Dementia; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Dermatologic Agents; Dimethyl Fumarate
• Other Study ID Numbers: 010622; 2022-002171-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No