Effects of Sulforaphane in Patients With Prodromal to Mild Alzheimer's Disease

Randomized,Double-blind, Placebo-controlled, Efficacy and Safety Study of Sulforaphane in Patients With Prodromal to Mild Alzheimer's Disease

In this proposed study, the investigators will evaluate the efficacy, safety and related mechanism of sulforaphane in treatment of Alzheimer's disease (AD). The study will recruit 160 AD patients, and then these patients will be randomized to sulforaphane group or placebo group (80 patients per arm) for 24 weeks clinic trial. Clinical efficacy and safety assessment will be done at screen/baseline, 4 week, 12 week, and 24 week. The specific aims are to compare sulforaphane versus placebo on: clinical core symptoms; biological samples also will be collected, and stored to research related mechanisms. During the study period, safety index including blood and urine routine, liver and kidney function, coagulation index and clinical effect index about neuropsychological scales will be recorded.

Study Overview

• Status: Unknown
• Conditions: Alzheimer Disease
• Intervention / Treatment: Dietary supplement: sulforaphane; Dietary supplement: Placebo

Detailed Description

In this proposed study, the investigators will evaluate the efficacy, safety and related mechanism of sulforaphane in treatment of AD. The study will recruit 160 AD patients, then these patients will be randomized to sulforaphane group or placebo group (80 patients per arm) for 24 weeks clinic trial. Clinical efficacy and safety assessment will be done at screen/baseline, 4 week, 12 week, 24 week. The specific aims are to compare sulforaphane versus placebo on: 1) clinical core symptoms; The investigators hypothesize that (1) sulforaphane is superior to placebo in the treatment of clinical symptoms in patients with AD, measured by the ADAS-cog, MMSE Scale, Moca; (2) Biological samples will be collected, and stored so that the hypothesis sulforaphane may alter oxidative stress indexes or inflammatory biomarkers, and influence histone deacetylase inhibitor mechanism or inflammatory mechanism et al that may be significantly correlated with clinical improvement. (3) Safety index including blood and urine routine, liver and kidney function, coagulation index and clinical effect index about neuropsychological scales will be recorded.

• Study Type: Interventional
• Enrollment (Anticipated): 160
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Qing-Qing tao, Ph.D; Phone Number: +08613777820430; Email: qingqingtao@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310009
      • Recruiting
      • Second Affiliated Hospital,Zhejiang University School of Medicine
      • Contact: Zhi-Ying Wu, MD&PhD; Phone Number: +86-571-87783569; Email: zhiyingwu@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1. Age range from 50 to 75 (including 50 and 75 years old), regardless of ethnic group or gender;
• 2. The subjects should be able to complete the cognitive ability measurement and other tests specified in the protocol;
• 3. Meeting the criteria for likely Alzheimer's Disease （AD） dementia (2011) by National Institute of Neurological Disorders and Strokes - Alzheimer's Disease and Related Diseases Association（NINCDS-ADRDA）;
• 4. Patients with mild dementia: the total score of Mini-Mental State Examination (MMSE) : ≥22 points; Clinical Dementia Rating scale （CDR）score > or equal to 0.5 and < or equal to1；The MMSE score provides evidence of mild disease severity and the CDR-GS score indicates that the patients have noticeable amnestic (pAD) or cognitive and functional (mAD) deficits
• 5. The total score of the Hachinski Ischemic Score （HIS ）was < 4.
• 6. Hamilton depression scale (17 items) total score ≤7 points;
• 7. Brain MRI shows a high likelihood of AD;
• 8. Before enrollment, patients should take a stable dose of dementia drugs (donepezil 5mg) ≥8 weeks;
• 9. The expected survival time is > 1 year;
• 10. Subjects should have a stable and reliable caregiver, or at least have frequent contact with the caregiver (at least 3 days per week and at least 2 hours per day), who will help patients participate in the whole study; Caregivers must accompany the subjects to the visit and assist in completing the relevant scale.

Exclusion Criteria:

• 1. Refuse to sign the inform consent form;
• 2. Other causes of dementia: known vascular, central nervous system infection ,Parkinson's disease, traumatic brain dementia, other physical and chemical factors; serious body disease , intracranial space-occupying lesions, endocrine system disease, such as thyroid disease, and a lack of vitamin B12, folic acid, or any other known causes of dementia.
• 3. Central nervous system diseases (including stroke, optic neuromyelitis, Parkinson's disease, epilepsy, etc.);
• 4. Obvious positive signs of nervous system examination;
• 5. Psychotic patients, including schizophrenia or other disorders with bipolar disorder, major depression or delirium;
• 6. Uncontrolled hypertension or hypotension during screening: systolic blood pressure ≥180（millimetres of mercury ）mmHg or < 90mmhg, or diastolic blood pressure ≥120mmHg or < 60mmhg;
• 7. Unstable or severe diseases of the heart, lung, liver, kidney and hematopoietic system according to the judgment of the researchers;
• 8. Patients with incurable visual and auditory disorders that cannot complete neuropsychological tests and scales;
• 9. Female subjects who are positive in pregnancy test or breast-feeding and who cannot take effective contraceptive measures or have a birth plan;
• 10. Severe allergy, non-allergic drug reaction or multi-drug allergy history;
• 11. Participated in other clinical trials within 3 months before screening visit;
• 12. Taking any health care products related to brain and brain improvement currently and failing to keep the promise to stop using the above products;
• 13. Other conditions are unsuitable for participating in this study according to the judgement of researchers.

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: sulforaphane group; The patients will take sulforaphane for 24 weeks, 2550mg once a day.	Dietary supplement: sulforaphane; Sulforaphane take 2550mg once a day.
Placebo Comparator: Placebo group; The patients will take placebo for 24 weeks, 2550mg once a day.	Dietary supplement: Placebo; Placebo take 2550mg once a day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Alzheimer's Disease Assessment Scale	The Alzheimer's Disease Assessment Scale (ADAS-cog) will be performed to test the cognition of patients at the enrollment, week 12 and week 24. The score ranges from 0 to 75，and higher values represent a better outcome.	From baseline to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alzheimer's Disease Collaborative research group-Activities of Daily Living scores.	Alzheimer's Disease Collaborative research group-Activities of Daily Living scores (ADCS-ADL) will be performed to test the activities of patients at the enrollment,week 6 and week12.The score ranges from 0 to 54，and higher values represent a better outcome.	From baseline to 24 weeks
Neuropsychiatric Inventory scores	Neuropsychiatric Inventory scores (NPI) will be performed to test the mental symptoms of patients at the enrollment and week12.The score ranges from 0 to 144，and higher values represent a worse outcome.	baseline time to 24 weeks
Mini-Mental State Examination scores	Mini-Mental State Examination scores(MMSE) will be performed to test the cognition of patients at the enrollment and week12.The score ranges from 0 to 30，and higher values represent a better outcome.	baseline time to 24 weeks
Montreal Cognitive Assessment scores	Montreal Cognitive Assessment scores (MoCA) will be performed to test the cognition of patients at the enrollment and week12.The score ranges from 0 to 30，and higher values represent a better outcome.	baseline time to 24 weeks
Clinician Interview-Based Impression of Change plus caregiver input	Clinician Interview-Based Impression of Change plus caregiver input (CIBIC-plus) is widely used in antidementia drug trials. It comprises Likert scales for disease severity and changes, and written accounts summarizing semistructured interviews evaluating behavior, cognition, and function.	baseline time to 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxidative stress indexes	The change of Oxidative stress indexes as tested by Oxidative stress indexes detection kit	At baseline and 24 week/endpoint
Epigenetics indicators	The change of Epigenetics indicators as tested by Epigenetics indicators	At baseline and 24 week/endpoint
Cytokines & Chemokines	The change of Cytokines & Chemokines as tested by Cytokines & Chemokines detection kit	At baseline and 24 week/endpoint
Metabolites	The change of Metabolites as tested by Metabolites detection kit	At baseline and 24 week/endpoint
RNA expression	The change of RNA expression as tested by RNA expression detection kit	At baseline and 24 week/endpoint
Intestinal microflora	The change of intestinal microflora as tested by Metagenomic technique	At baseline and 24 week/endpoint

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

Publications and helpful links

General Publications

• Lee S, Choi BR, Kim J, LaFerla FM, Park JHY, Han JS, Lee KW, Kim J. Sulforaphane Upregulates the Heat Shock Protein Co-Chaperone CHIP and Clears Amyloid-beta and Tau in a Mouse Model of Alzheimer's Disease. Mol Nutr Food Res. 2018 Jun;62(12):e1800240. doi: 10.1002/mnfr.201800240. Epub 2018 May 28.
• Hou TT, Yang HY, Wang W, Wu QQ, Tian YR, Jia JP. Sulforaphane Inhibits the Generation of Amyloid-beta Oligomer and Promotes Spatial Learning and Memory in Alzheimer's Disease (PS1V97L) Transgenic Mice. J Alzheimers Dis. 2018;62(4):1803-1813. doi: 10.3233/JAD-171110.
• Jhang KA, Park JS, Kim HS, Chong YH. Sulforaphane rescues amyloid-beta peptide-mediated decrease in MerTK expression through its anti-inflammatory effect in human THP-1 macrophages. J Neuroinflammation. 2018 Mar 12;15(1):75. doi: 10.1186/s12974-018-1112-x.
• Kim J, Lee S, Choi BR, Yang H, Hwang Y, Park JH, LaFerla FM, Han JS, Lee KW, Kim J. Sulforaphane epigenetically enhances neuronal BDNF expression and TrkB signaling pathways. Mol Nutr Food Res. 2017 Feb;61(2). doi: 10.1002/mnfr.201600194. Epub 2016 Nov 30.
• Zhao F, Zhang J, Chang N. Epigenetic modification of Nrf2 by sulforaphane increases the antioxidative and anti-inflammatory capacity in a cellular model of Alzheimer's disease. Eur J Pharmacol. 2018 Apr 5;824:1-10. doi: 10.1016/j.ejphar.2018.01.046. Epub 2018 Jan 31.
• Zhang R, Zhang J, Fang L, Li X, Zhao Y, Shi W, An L. Neuroprotective effects of sulforaphane on cholinergic neurons in mice with Alzheimer's disease-like lesions. Int J Mol Sci. 2014 Aug 18;15(8):14396-410. doi: 10.3390/ijms150814396.

Study record dates

Study Major Dates

• Study Start (Anticipated): May 10, 2020
• Primary Completion (Anticipated): November 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: November 13, 2019
• First Submitted That Met QC Criteria: December 24, 2019
• First Posted (Actual): December 30, 2019

Study Record Updates

• Last Update Posted (Actual): May 12, 2020
• Last Update Submitted That Met QC Criteria: May 9, 2020
• Last Verified: May 1, 2019

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; Physiological Effects of Drugs; Antineoplastic Agents; Protective Agents; Anticarcinogenic Agents; Sulforaphane
• Other Study ID Numbers: Wulab-AD sulforaphane

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

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