Efficacy and Safety of Dimethyl Fumarate in Reducing Brain Atrophy and Improving Cognitive Function in Alzheimer's Disease-Related Mild Cognitive Impairment

Trial ID: 2024-517214-16-00
Protocol: 010622
Sponsor: Medical University Of Lodz

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Diseases & Conditions

Dementia Alzheimer's type

Objectives

The primary objective of this randomized, double-blind, placebo-controlled trial is the **assessment** of the degree of improvement in **cognitive functions**, including memory, attention, thinking, executive, and language functions in patients diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD) receiving dimethyl fumarate at a dose of 480 mg daily compared to patients taking placebo. This objective is clinically relevant as it aims to determine the efficacy of dimethyl fumarate in enhancing cognitive abilities, which are crucial for the quality of life and daily functioning of patients with MCI and AD.

Secondary objectives include:

Assessment of the impact of therapy on the daily functioning of patients using the ADCS-ADL Scale.
Evaluation of the effect of therapy on the presence of neuropsychiatric symptoms and behavioral disorders using the NPI and GDS scales.
Assessment of the impact of therapy on the quality of life of patients and their caregivers using the EQ-5D scales and Zarit Burden Interview.
Evaluation of the effect of therapy on the reduction of brain atrophy in patients from the active group compared to the control group using MRI tests.
Assessment of the impact of therapy on the improvement of functional connections assessed in rs-fMRI and rs-EEG.
Evaluation of the effect of therapy on peripheral markers of oxidative stress and pro-inflammatory markers.
Assessment of the degree of reduction in the rate of MCI progression to dementia after the end of the clinical phase of the study.
Evaluation of the degree of improvement in cognitive functions using the MMSE and CDR scales.
Safety assessment of the treatment.

Participants

The clinical trial involves **participants** diagnosed with **Alzheimer’s disease**, specifically those with mild cognitive impairment and mild to moderate dementia. The study population includes both men and women aged between 55 and 90 years. Participants are required to have a Mini-Mental State Examination (MMSE) score ranging from 17 to 30 points and a Clinical Dementia Rating (CDR) score from 0.5 to 2. All participants must have completed a minimum of six years of education. The trial includes individuals who have been on a stable dose of cholinesterase inhibitors for at least 60 days or memantine for at least three months prior to study inclusion. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants must have a close person or actual guardian to assist them during the study. The selection criteria ensure that the study population is well-defined and appropriate for assessing the cognitive improvements associated with the intervention. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **dimethyl fumarate** in patients with mild cognitive impairment and dementia due to **Alzheimer's disease**. The primary objective is to assess the improvement in cognitive functions, including memory, attention, thinking, executive, and language functions, in patients receiving dimethyl fumarate at a daily dose of 480 mg compared to those receiving a placebo. The trial is set to last for a total duration of 52 weeks, with participant involvement expected to span this entire period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (55-90 years), diagnosis of mild cognitive impairment or mild to moderate dementia in Alzheimer's disease, and a Mini-Mental State Examination (MMSE) score between 17 and 30. Following the screening, participants will be randomized to receive either dimethyl fumarate or a placebo. Regular follow-up visits will be scheduled to monitor the participants' cognitive functions, daily functioning, neuropsychiatric symptoms, quality of life, and any adverse events. These assessments will utilize tools such as the RBANS, ADCS-ADL scale, NPI, GDS scale, EQ-5D scales, and Zarit Burden Interview.

The end-of-study visit will mark the conclusion of the trial, where final assessments will be conducted to evaluate the primary and secondary endpoints. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial is anticipated to commence recruitment on October 14, 2024, and is expected to conclude by June 30, 2026. This study is categorized as a Phase 4 trial, focusing on the long-term effects and safety of dimethyl fumarate in the specified patient population.

Treatment

The clinical trial involves the administration of **dimethyl fumarate**, an experimental medication, to evaluate its efficacy and safety in patients with mild cognitive impairment and dementia due to Alzheimer's disease. **Dimethyl fumarate** is provided in the form of gastro-resistant capsules, hard, and is administered orally. The dosage for the trial is set at 480 mg per day. The maximum treatment period for participants is 52 weeks. The total maximum dose that a participant may receive over the course of the study is 173,040 mg. The trial is designed to be randomized, double-blind, and placebo-controlled, ensuring that neither the participants nor the investigators know who is receiving the active medication or the placebo, thus maintaining the integrity of the study results.

The comparator treatment in this study is a placebo, which is used to assess the true efficacy of **dimethyl fumarate** by providing a baseline for comparison. The placebo is administered in a manner identical to the experimental medication, ensuring that participants in both groups receive capsules that are indistinguishable in appearance and administration schedule. This approach helps to eliminate bias and allows for a clear evaluation of the medication's impact on cognitive functions, brain atrophy reduction, synaptic functional connectivity, quality of life, and activities of daily living.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen. This is crucial for maintaining the validity of the trial results and for accurately assessing the safety and efficacy of **dimethyl fumarate**. Compliance monitoring may involve regular check-ins, pill counts, or electronic monitoring devices, although specific methods are not detailed in the provided data.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the assessment of cognitive function improvement, measured by the RBANS scores, in patients diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD) after completing therapy with **dimethyl fumarate** compared to a placebo group. Secondary endpoints include the evaluation of daily functioning using the ADCS-ADL scale, the presence of neuropsychiatric symptoms and behavioral disorders using the NPI and GDS scales, and the quality of life of patients and their caregivers assessed through the EQ-5D scales and Zarit Burden Interview. Additionally, the trial will assess the expression of peripheral markers of oxidative stress and pro-inflammatory markers, as well as cognitive function improvements using MMSE and CDR scores. The difference in frequency and severity of reported adverse events between the active and placebo groups will also be evaluated.

The trial is designed as a randomized, double-blind, placebo-controlled study. Efficacy parameters will be collected and analyzed at specified timepoints throughout the trial, with the maximum treatment period set at 52 weeks. The trial aims to provide a comprehensive evaluation of the efficacy of dimethyl fumarate in improving cognitive functions and overall quality of life in patients with MCI and AD.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Men and women aged 55-90.
Patients diagnosed with mild cognitive impairment in Alzheimer's disease and mild to moderate dementia in Alzheimer's disease (MMSE> 16) diagnosed according to NIA-AA criteria.
MMSE score from 17 to 30 points.
CDR score from 0.5 to 2.
Signing by the patient of informed, voluntary consent to participate in the study.
The patient has a close person / actual guardian who agrees to help the patient during the participation in the study.
Minimum 6 years of education.
For anti-Alzheimer's drugs, cholinesterase inhibitors are acceptable were included at least 3 months prior to study inclusion and used at a stable dose for at least 60 days prior to study inclusion. For memantine, its use is acceptable when it is included at least 4 months prior to study inclusion and used at a stable dose for at least 3 months prior to study inclusion.

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Exclusion Criteria

Lack of informed consent to participate in the study.
Inability to read or write.
Women who are pregnant, breastfeeding or of childbearing age not using effective contraception (hormonal contraception, surgical sterilization, intrauterine device, condom in combination with vaginal spermicide).
Participation in another clinical trial, currently or within 3 months before the screening visit.
Liver failure (ie cirrhosis or active liver disease), diagnosed acute or chronic hepatitis, regardless of the cause.
Chronic kidney disease with elevated serum creatinine value > 115umol/l (1,3 mg/dL).
Abnormal results of hepatic parameters: ALT> 2 times upper limit of normal,
Leukopenia (<4000 / mm3), granulocytopenia (<1500 / mm3) or lymphopenia (<1000 / mm3) from any cause.
Severe agitation.
Mental retardation.
Delirium diagnosed according to DSM-5 criteria.
Diagnosis of neurological and neurodegenerative diseases other than Alzheimer's disease (multiple sclerosis, Parkinson's disease, Huntington's disease, previous stroke).
Presence of MRI haemorrhagic foci ≥ 2 cm3 in diameter, more than three (3) ischemic foci ≥ 1.5 cm3 in diameter or a single ischemic focus ≥ 2 cm3, presence of vascular malformations, aneurysms, subdural hematoma, normotensive hydrocephalus, the final decision is at the discretion of the researcher.
Severe or uncontrolled physical disease that could interfere with the course of the study (e.g., cancer, cardiovascular, respiratory, metabolic or digestive, severe renal failure, unstable type I or II diabetes, untreated or uncontrolled clinically significant arterial hypertension) .
Use of benzodiazepines or barbiturates one week prior to screening.
Pharmacological immunosuppression.
Patients with bipolar disorder or psychotic disorder or any other psychiatric condition (current or past) that the Investigator considers to be interfering with the study.
Alcoholism, benzodiazepine dependence or drug dependence as defined by DSM-5 in the last 5 years (addicted for more than one year and or in remission for less than 3 years).
Patients with any medical condition that the investigator considers to be an exclusion criterion.
Treatment with thyroid hormones started, stopped or modified within the 3 months prior to the selection visit.
Treatment of menopause with hormone replacement therapy, started, stopped or modified within the 3 months prior to the screening visit.
Use of drugs not allowed in the study (each time to be decided by the investigator): immunosuppressive anticancer agents, immunosuppressants, ethyl ester corticosteroids applied orally or topically and live attenuated vaccines. Inactivated vaccines can be used.