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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medical University Of Lodz

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

Trial duration

28 Oct 2024 → ongoing

Decision date (initial)

2024-11-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Medical Research Agency

External identifiers

EU CT number

2024-517214-16-00

EudraCT number

2022-002171-11

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Assessment of the degree of improvement in cognitive functions, including memory, attention, thinking, executive and language functions in patients diagnosed with MCI and AD receiving dimethyl fumarate at a dose of 480 mg daily compared to patients taking placebo

Secondary objectives 9

1. Assessment of the impact of therapy on the daily functioning of patients - ADCS-ADL Scale,
2. Assessment of the effect of therapy on the presence of neuropsychiatric symptoms / behavioral disorders in patients - NPI scale, GDS scale
3. Assessment of the impact of therapy on the quality of life of patients and their caregivers (EQ-5D scales; Zarit Burden Interview),
4. 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 test),
5. Assessment of the impact of therapy on the improvement of functional connections assessed in rs-fMRI and in rs-EEG,
6. Assessment of the effect of therapy on peripheral markers of oxidative stress and pro-inflammatory markers,
7. Assessment of the degree of reduction in the rate of MCI progression to dementia after the end of the clinical phase of the study,
8. Assessment of the degree of improvement in cognitive functions using the MMSE and CDR scales
9. Safety assessment of the treatment

Conditions and MedDRA coding

Alzheimer’s disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Men and women aged 55-90.
2. 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.
3. MMSE score from 17 to 30 points.
4. CDR score from 0.5 to 2.
5. Signing by the patient of informed, voluntary consent to participate in the study.
6. The patient has a close person / actual guardian who agrees to help the patient during the participation in the study.
7. Minimum 6 years of education.
8. 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.

Exclusion criteria 22

1. Lack of informed consent to participate in the study.
2. Inability to read or write.
3. 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).
4. Participation in another clinical trial, currently or within 3 months before the screening visit.
5. Liver failure (ie cirrhosis or active liver disease), diagnosed acute or chronic hepatitis, regardless of the cause.
6. Chronic kidney disease with elevated serum creatinine value > 115umol/l (1,3 mg/dL).
7. Abnormal results of hepatic parameters: ALT> 2 times upper limit of normal,
8. Leukopenia (<4000 / mm3), granulocytopenia (<1500 / mm3) or lymphopenia (<1000 / mm3) from any 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 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.
14. 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) .
15. Use of benzodiazepines or barbiturates one week prior to screening.
16. Pharmacological immunosuppression.
17. 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.
18. 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).
19. Patients with any medical condition that the investigator considers to be an exclusion criterion.
20. Treatment with thyroid hormones started, stopped or modified within the 3 months prior to the selection visit.
21. Treatment of menopause with hormone replacement therapy, started, stopped or modified within the 3 months prior to the screening visit.
22. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in cognitive performance as assessed by RBANS scores between the post-treatment visit (V9) and the randomisation visit (V1).

Secondary endpoints 6

1. Assessment of the daily functioning of patients based on the ADCS-ADL scale
2. Assessment of the presence of neuropsychiatric symptoms / behavioral disorders in patients using the NPI, GDS scale),
3. Assessment of the quality of life of patients and their caregivers based on the EQ-5D scales, Zarit Burden Interview,
4. Assessment of the expression of peripheral markers of oxidative stress and pro-inflammatory markers.
5. Improvement of cognitive functions using MMSE, CDR in patients diagnosed with MCI and AD receiving dimethyl fumarate after the end of therapy compared to the placebo group.
6. Difference in frequency and severity of reported adverse events in the active group versus the placebo group.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medical University Of Lodz

Sponsor organisation

Medical University Of Lodz

Address

Al. Tadeusza Kosciuszki 4

City

Lodz

Postcode

90-419

Country

Poland

Scientific contact point

Organisation

Medical University Of Lodz

Contact name

Jakub Kaźmierski

Public contact point

Organisation

Medical University Of Lodz

Contact name

Katarzyna Wiklak-Mrowińska

Third parties 1

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications