Daphnetin Capsule In the Treatment of VaScular COgnitive Impairment Without Dementia

NCT ID: NCT06507488

Last Updated: 2025-08-28

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 206 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-07-07
• Study Completion Date: 2026-04-30

Brief Summary

The purpose of this clinical trial is to understand and evaluate the clinical efficacy and safety of Daphnetin Capsule in patients with vascular cognitive impairment. Changes in the Vascular Dementia Assessment Scale-cog(VADAS-cog) at 6 months were evaluated. Although Daphnetin has a dual neurovascular protective effect, however, there is still a lack of relevant high-quality studies on its role in patients with vascular cognitive impairment, especially in patients with vascular cognitive impairment in non-dementia (VCI-ND), whether it has a role in improving cognitive status needs to be urgently explored in high-quality clinical studies. Researchers are comparing Daphnetin to placebo (a drug-free analog) to see if Daphnetin is effective in treating vascular cognitive impairment. Participants will take either Daphnetin or placebo daily for six months, with follow-up visits every three months and completion of a case report form.

Detailed Description

Vascular cognitive impairment (VCI) is caused by ischemic or hemorrhagic strokes and other cerebrovascular diseases, leading to cognitive and memory function impairment. With the aging population and high incidence of cerebrovascular diseases in China, Vascular cognitive impairment (VCI) prevalence is rising, increasing the disease burden. However, due to the complexity of Vascular cognitive impairment (VCI) symptoms and imaging changes, targeted therapies are currently lacking.

Daphnetin, a coumarin derivative, has shown promise in treating various diseases and has gained significant attention recently. It offers "triple protection" for blood, blood vessels, and ischemic tissues by inhibiting inflammation, anticoagulation, and thrombosis, protecting endothelial structures, and regulating vasoactive substances. Daphnetin is particularly beneficial for cardio-cerebral vascular disease, diabetes mellitus, and microvascular complications. It also expands peripheral blood vessels, improving circulation and alleviating vascular occlusive diseases.

Research indicates that Daphnetin's anti-inflammatory effects can inhibit neuroinflammation, promote synaptic growth, and enhance neuronal survival, protecting nerve cells and repairing damage. Despite these benefits, there is a lack of high-quality studies on Daphnetin's role in non-dementia vascular cognitive impairment (VCI-ND).

This project aims to evaluate the clinical efficacy and safety of oral Daphnetin capsules in treating Vascular cognitive impairment (VCI) through a prospective, randomized, double-blind, placebo-controlled study. Patients with vascular cognitive dysfunction confirmed by cerebral small vessel disease imaging will participate. The study will follow the international FINESSE framework, comparing Daphnetin to a placebo over six months, with follow-up visits and case report forms completed every three months.

Conditions

Cerebrovascular Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Daphnetin

oral Daphnetin Capsule three capsules/tid for up to six months.

Group Type: EXPERIMENTAL

Daphnetin Capsule

Intervention Type: DRUG

Daphnetin, chemically known as 7,8-dihydroxycoumarin, also known as ZuShiMaJiaSu, is a class of coumarin derivatives derived from different Daphnetin genus plant .

Placebo

oral Placebo (Daphnetin Capsule simulants) three capsules/tid for up to six months.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

The placebo is a Daphnetin Capsule simulants

Interventions

Daphnetin Capsule

Daphnetin, chemically known as 7,8-dihydroxycoumarin, also known as ZuShiMaJiaSu, is a class of coumarin derivatives derived from different Daphnetin genus plant .

Intervention Type: DRUG

Placebo

The placebo is a Daphnetin Capsule simulants

Intervention Type: DRUG

Other Intervention Names

7,8-dihydroxycoumarin

Eligibility Criteria

Inclusion Criteria

1. Be 50-80 years of age (both ends included)

2. Have a complaint of cognitive impairment involving memory and/or other cognitive domains that has persisted for at least 3 months

3. Have a cognitive level that is neither normal nor demented according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Criteria ( DSM-V criteria）, a Montreal Cognitive Assessment (MoCA scale) score <26 and ≥18, and a Clinical Dementia Rating (CDR) scale score of ≥0.5 in at least one domain and an overall CDR score ≤1

4. Have a cognitive level that is neither normal nor demented according to DSM-V criteria, a MoCA scale score <26 and ≥18, and a CDR scale score of ≥0.5 in at least one domain and an overall CDR score ≤1

5. Voluntarily participate in this study and sign an informed consent form.

Exclusion Criteria

1. Previously diagnosed dementia; vascular cognitive impairment not associated with a condition other than dementia that may affect cognition

2. Acute stroke event within 6 months

3. Previously diagnosed hereditary or inflammatory small vessel disease

4. Presence of congenital mental retardation and severe neurological or psychiatric disorders

5. Illiteracy or severe visual or hearing impairment, severe aphasia, and other factors that may preclude cooperation with neuropsychological evaluation

6. Associated depression (Hamilton Depression Scale score ≥ 17), or other unrelated serious mental illness (schizophrenia, bipolar disorder, or delirium)

7. Combined severe cardiac, pulmonary, and renal insufficiency (creatinine > 2.0 mg/dl or 177 μ mol/L), and severe hepatic impairment (aminotransferases more than 3 times normal)

8. Alcoholism, drug addiction, or ongoing use of medications that affect cognitive assessment, such as tranquilizers, sleeping pills, puberty pills, and cholinergics

9. Malignant tumors that have been clearly diagnosed, vital organ failure

10. Those with bleeding tendency after surgery

11. Pregnant and lactating women are prohibited

12. Severe hypertension (Systolic Blood Pressure(SBP)≥160mmHg and/or Diastolic Blood Pressure(DBP)≥110mmHg) is prohibited

13. Previous allergy or intolerance to the ingredients of Reserpine

14. The subject does not have a stable and reliable caregiver or the caregiver is unable to assist the subject in participating in the study

15. Patients who have participated in other interventional clinical studies within the last 3 months or are currently participating in other interventional clinical studies.

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Fourth People's Hospital of Shenyang

UNKNOWN

Sponsor Role: collaborator

First People's Hospital of Shenyang

OTHER

Sponsor Role: lead

Responsible Party

Dr. Yi Sui

vice president

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Yi Sui, MD PhD

Role: PRINCIPAL_INVESTIGATOR

The Fourth People's Hospital of Shenyang, China Medical University

Locations

Shenyang First People's Hospital

Shenyang, Liaoning, China

Site Status: RECRUITING

Countries

China

Central Contacts

Yi Sui, MD PhD

Role: CONTACT

jakeyisui@icloud.com

+86 24 86861329

Mingming Dong, MD

Role: CONTACT

dongming_ming@126.com

+86 24 86861329

Facility Contacts

Li Li, MD PhD

Role: primary

lily720823@163.com

+86 24 31956000

Xinze Guo, MD

Role: backup

176953982@qq.com

+86 24 31956000

References

Benisty S. [Current concepts in vascular dementia]. Geriatr Psychol Neuropsychiatr Vieil. 2013 Jun;11(2):171-80. doi: 10.1684/pnv.2013.0410. French.

Reference Type: BACKGROUND

PMID: 23803634 (View on PubMed)

Wu YT, Lee HY, Norton S, Chen C, Chen H, He C, Fleming J, Matthews FE, Brayne C. Prevalence studies of dementia in mainland china, Hong Kong and taiwan: a systematic review and meta-analysis. PLoS One. 2013 Jun 11;8(6):e66252. doi: 10.1371/journal.pone.0066252. Print 2013.

Reference Type: BACKGROUND

PMID: 23776645 (View on PubMed)

D'Onofrio G, Sancarlo D, Addante F, Ciccone F, Cascavilla L, Paris F, Picoco M, Nuzzaci C, Elia AC, Greco A, Chiarini R, Panza F, Pilotto A. Caregiver burden characterization in patients with Alzheimer's disease or vascular dementia. Int J Geriatr Psychiatry. 2015 Sep;30(9):891-9. doi: 10.1002/gps.4232. Epub 2014 Dec 4.

Reference Type: BACKGROUND

PMID: 25475248 (View on PubMed)

Kalaria RN. The pathology and pathophysiology of vascular dementia. Neuropharmacology. 2018 May 15;134(Pt B):226-239. doi: 10.1016/j.neuropharm.2017.12.030. Epub 2017 Dec 19.

Reference Type: BACKGROUND

PMID: 29273521 (View on PubMed)

Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, Willis RJ, Wallace RB. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology. 2007;29(1-2):125-32. doi: 10.1159/000109998. Epub 2007 Oct 29.

Reference Type: BACKGROUND

PMID: 17975326 (View on PubMed)

Javed M, Saleem A, Xaveria A, Akhtar MF. Daphnetin: A bioactive natural coumarin with diverse therapeutic potentials. Front Pharmacol. 2022 Sep 29;13:993562. doi: 10.3389/fphar.2022.993562. eCollection 2022.

Reference Type: BACKGROUND

PMID: 36249766 (View on PubMed)

Singh L, Singh AP, Bhatti R. Mechanistic interplay of various mediators involved in mediating the neuroprotective effect of daphnetin. Pharmacol Rep. 2021 Oct;73(5):1220-1229. doi: 10.1007/s43440-021-00261-z. Epub 2021 Apr 16.

Reference Type: BACKGROUND

PMID: 33860917 (View on PubMed)

Chaudhary PK, Kim S, Kim S. Antiplatelet Effect of Daphnetin Is Regulated by cPLA2-Mediated Thromboxane A2 Generation in Mice. Int J Mol Sci. 2023 Mar 17;24(6):5779. doi: 10.3390/ijms24065779.

Reference Type: BACKGROUND

PMID: 36982853 (View on PubMed)

Syed AM, Kundu S, Ram C, Kulhari U, Kumar A, Mugale MN, Mohapatra P, Murty US, Sahu BD. Up-regulation of Nrf2/HO-1 and inhibition of TGF-beta1/Smad2/3 signaling axis by daphnetin alleviates transverse aortic constriction-induced cardiac remodeling in mice. Free Radic Biol Med. 2022 Jun;186:17-30. doi: 10.1016/j.freeradbiomed.2022.04.019. Epub 2022 May 2.

Reference Type: BACKGROUND

PMID: 35513128 (View on PubMed)

Yang F, Jiang X, Cao H, Shuai W, Zhang L, Wang G, Quan D, Jiang X. Daphnetin Preconditioning Decreases Cardiac Injury and Susceptibility to Ventricular Arrhythmia following Ischaemia-Reperfusion through the TLR4/MyD88/NF-Kappab Signalling Pathway. Pharmacology. 2021;106(7-8):369-383. doi: 10.1159/000513631. Epub 2021 Apr 26.

Reference Type: BACKGROUND

PMID: 33902056 (View on PubMed)

Yang Y, Sheng Q, Nie Z, Liu L, Zhang W, Chen G, Ye F, Shi L, Lv Z, Xie J, Wang D. Daphnetin inhibits spinal glial activation via Nrf2/HO-1/NF-kappaB signaling pathway and attenuates CFA-induced inflammatory pain. Int Immunopharmacol. 2021 Sep;98:107882. doi: 10.1016/j.intimp.2021.107882. Epub 2021 Jun 26.

Reference Type: BACKGROUND

PMID: 34182245 (View on PubMed)

Du G, Tu H, Li X, Pei A, Chen J, Miao Z, Li J, Wang C, Xie H, Xu X, Zhao H. Daphnetin, a natural coumarin derivative, provides the neuroprotection against glutamate-induced toxicity in HT22 cells and ischemic brain injury. Neurochem Res. 2014 Feb;39(2):269-75. doi: 10.1007/s11064-013-1218-6. Epub 2013 Dec 17.

Reference Type: BACKGROUND

PMID: 24343531 (View on PubMed)

Yu W, Wang H, Ying H, Yu Y, Chen D, Ge W, Shi L. Daphnetin attenuates microglial activation and proinflammatory factor production via multiple signaling pathways. Int Immunopharmacol. 2014 Jul;21(1):1-9. doi: 10.1016/j.intimp.2014.04.005. Epub 2014 Apr 18.

Reference Type: BACKGROUND

PMID: 24747094 (View on PubMed)

Zhi J, Duan B, Pei J, Wu S, Wei J. Daphnetin protects hippocampal neurons from oxygen-glucose deprivation-induced injury. J Cell Biochem. 2019 Mar;120(3):4132-4139. doi: 10.1002/jcb.27698. Epub 2018 Sep 27.

Reference Type: BACKGROUND

PMID: 30260007 (View on PubMed)

Wang D, Zhu B, Liu X, Han Q, Ge W, Zhang W, Lu Y, Wu Q, Shi L. Daphnetin Ameliorates Experimental Autoimmune Encephalomyelitis Through Regulating Heme Oxygenase-1. Neurochem Res. 2020 Apr;45(4):872-881. doi: 10.1007/s11064-020-02960-0. Epub 2020 Jan 16.

Reference Type: BACKGROUND

PMID: 31950453 (View on PubMed)

Yang L, Yang Q, Zhang K, Li YJ, Wu YM, Liu SB, Zheng LH, Zhao MG. Neuroprotective effects of daphnetin against NMDA receptor-mediated excitotoxicity. Molecules. 2014 Sep 15;19(9):14542-55. doi: 10.3390/molecules190914542.

Reference Type: BACKGROUND

PMID: 25225718 (View on PubMed)

Yan L, Zhou X, Zhou X, Zhang Z, Luo HM. Neurotrophic effects of 7,8-dihydroxycoumarin in primary cultured rat cortical neurons. Neurosci Bull. 2012 Oct;28(5):493-8. doi: 10.1007/s12264-012-1233-7. Epub 2012 May 18.

Reference Type: BACKGROUND

PMID: 22961470 (View on PubMed)

Benjamin P, Zeestraten E, Lambert C, Ster IC, Williams OA, Lawrence AJ, Patel B, MacKinnon AD, Barrick TR, Markus HS. Progression of MRI markers in cerebral small vessel disease: Sample size considerations for clinical trials. J Cereb Blood Flow Metab. 2016 Jan;36(1):228-40. doi: 10.1038/jcbfm.2015.113.

Reference Type: BACKGROUND

PMID: 26036939 (View on PubMed)

Markus HS, van Der Flier WM, Smith EE, Bath P, Biessels GJ, Briceno E, Brodtman A, Chabriat H, Chen C, de Leeuw FE, Egle M, Ganesh A, Georgakis MK, Gottesman RF, Kwon S, Launer L, Mok V, O'Brien J, Ottenhoff L, Pendlebury S, Richard E, Sachdev P, Schmidt R, Springer M, Tiedt S, Wardlaw JM, Verdelho A, Webb A, Werring D, Duering M, Levine D, Dichgans M. Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE): A Review. JAMA Neurol. 2022 Nov 1;79(11):1187-1198. doi: 10.1001/jamaneurol.2022.2262.

Reference Type: BACKGROUND

PMID: 35969390 (View on PubMed)

Pendlebury ST, Mariz J, Bull L, Mehta Z, Rothwell PM. MoCA, ACE-R, and MMSE versus the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards Neuropsychological Battery after TIA and stroke. Stroke. 2012 Feb;43(2):464-9. doi: 10.1161/STROKEAHA.111.633586. Epub 2011 Dec 8.

Reference Type: BACKGROUND

PMID: 22156700 (View on PubMed)

Ghafar MZAA, Miptah HN, O'Caoimh R. Cognitive screening instruments to identify vascular cognitive impairment: A systematic review. Int J Geriatr Psychiatry. 2019 Aug;34(8):1114-1127. doi: 10.1002/gps.5136. Epub 2019 May 16.

Reference Type: BACKGROUND

PMID: 31050033 (View on PubMed)

Smith EE, Biessels GJ, De Guio F, de Leeuw FE, Duchesne S, During M, Frayne R, Ikram MA, Jouvent E, MacIntosh BJ, Thrippleton MJ, Vernooij MW, Adams H, Backes WH, Ballerini L, Black SE, Chen C, Corriveau R, DeCarli C, Greenberg SM, Gurol ME, Ingrisch M, Job D, Lam BYK, Launer LJ, Linn J, McCreary CR, Mok VCT, Pantoni L, Pike GB, Ramirez J, Reijmer YD, Romero JR, Ropele S, Rost NS, Sachdev PS, Scott CJM, Seshadri S, Sharma M, Sourbron S, Steketee RME, Swartz RH, van Oostenbrugge R, van Osch M, van Rooden S, Viswanathan A, Werring D, Dichgans M, Wardlaw JM. Harmonizing brain magnetic resonance imaging methods for vascular contributions to neurodegeneration. Alzheimers Dement (Amst). 2019 Feb 26;11:191-204. doi: 10.1016/j.dadm.2019.01.002. eCollection 2019 Dec.

Reference Type: BACKGROUND

PMID: 30859119 (View on PubMed)

Shi J, Wei M, Ni J, Sun F, Sun L, Wang J, Yu T, Wang K, Lv P, Wang Y, Zhang Y, Gao X, Gao X, Luo B, Mao S, Zhang B, Ren X, Yu F, Hu W, Yin P, Wu N, Liu X, Bi Q, Wang Y, Tian J; CHASE Study Group. Tianzhi granule improves cognition and BPSD of vascular dementia: a randomized controlled trial. J Transl Med. 2020 Feb 13;18(1):76. doi: 10.1186/s12967-020-02232-z.

Reference Type: BACKGROUND

PMID: 32054507 (View on PubMed)

Smith EE. Clinical presentations and epidemiology of vascular dementia. Clin Sci (Lond). 2017 Jun 1;131(11):1059-1068. doi: 10.1042/CS20160607.

Reference Type: BACKGROUND

PMID: 28515342 (View on PubMed)

Other Identifiers

RXSJNJLXD-2024-SYSY

Identifier Type: -

Identifier Source: org_study_id