Clinical trial NCT04213391: Effects of Sulforaphane in Patients With Prodromal to Mild Alzheimer's Disease
Official title: Randomized,Double-blind, Placebo-controlled, Efficacy and Safety Study of Sulforaphane in Patients With Prodromal to Mild Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Alzheimer Disease
Lead sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
Sponsor class: OTHER
First posted: 2019-12-30
Enrollment: 160
Sex: ALL
Minimum age (years): 50
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The Alzheimer's Disease Assessment Scale
timeFrame: From baseline to 24 weeks
Secondary outcomes:
measure: Alzheimer's Disease Collaborative research group-Activities of Daily Living scores.
timeFrame: From baseline to 24 weeks
measure: Neuropsychiatric Inventory scores
timeFrame: baseline time to 24 weeks
measure: Mini-Mental State Examination scores
timeFrame: baseline time to 24 weeks
measure: Montreal Cognitive Assessment scores
timeFrame: baseline time to 24 weeks
measure: Clinician Interview-Based Impression of Change plus caregiver input
timeFrame: baseline time to 24 weeks
Other outcomes:
measure: Oxidative stress indexes
timeFrame: At baseline and 24 week/endpoint
measure: Epigenetics indicators
timeFrame: At baseline and 24 week/endpoint
measure: Cytokines & Chemokines
timeFrame: At baseline and 24 week/endpoint
measure: Metabolites
timeFrame: At baseline and 24 week/endpoint
measure: RNA expression
timeFrame: At baseline and 24 week/endpoint
measure: Intestinal microflora
timeFrame: At baseline and 24 week/endpoint
Locations:
city: Hangzhou
country: China
facility: Second Affiliated Hospital,Zhejiang University School of Medicine
state: Zhejiang
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.