Clinical Significance of DKK2 Protein in Cerebral Ischemia-reperfusion Injury

NCT05585255 | Recruiting DMC

• 1 other identifier: NFEC-2022-273
• Study Type: observational
• Target: 108
• Locations: 1 country
• Sites: 2

Brief Summary

The study is a two-center prospective cohort clinical trial. The primary purpose of this trial is to identify the pattern of DKK2 serum levels in ischemic stroke patients after revascularization therapy and determine the correlation between serum DKK2 levels and prognosis.

Conditions

Ischemic Stroke, Acute; Ischemia-reperfusion Injury; Cerebral Edema

Outcome Measures

Primary Outcomes (1)

• 90-day Functional Outcome.

  The favorable prognosis (modified Rankin score \[mRS\] score ≤ 2) and the unfavorable prognosis group (\[mRS\] score ≥ 3) within 90 d after onset.

  The mRS score will follow up at 90 days.

Secondary Outcomes (5)

• Incidence of neurological deterioration

  The NIHSS score will evaluat at the point before revascularization treatment, 0 (immediately after revascularization treatment), 24, 48, 72 hours, and 7 days after revascularization treatment.

• Incidence of substantial hemorrhagic transformation

  At the point before revascularization treatment, 24, and 72 hours after revascularization treatment.

• The severity of cerebral edema.

  At the point before revascularization treatment, 24, and 72 hours after revascularization treatment.

• Incidence of midline shift ≥ 6mm.

  At the point before revascularization treatment, 24, and 72 hours after revascularization treatment.

• Levels of major inflammatory indicators in peripheral blood.

  Before revascularization treatment, 24, 48, 72 hours and 7 days after revascularization treatment.

Study Arms (1)

Acute ischemic stroke patients

Acute ischemic stroke patients with large vessel occlusion who received mechanical thrombectomy therapy and are successfully revascularized

Diagnostic Test: enzyme-linked immunosorbent assay(ELISA)

Interventions

enzyme-linked immunosorbent assay(ELISA) DIAGNOSTIC_TEST

After allowing to stand at room temperature for 2h, blood samples are centrifuged at 4 ℃ for 15 min (12000 rpm) to collect the supernatant. Then, the levels of DKK2, IL-6, IL-1β, TNF-α, and IL-10 in the supernatants are tested by ELISA detection.

Acute ischemic stroke patients

Eligibility Criteria

• Age: 18 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Acute ischemic stroke patients with large vessel occlusion who are treated with mechanical embolization and successfully revascularized at Dongguan Hospital of Southern Medical University and Nanfang Hospital of Southern Medical University.

You may qualify if:

• Age ≥ 18 years, \< 80 years, sex not limited;
• Definite clinical diagnosis of acute ischemic stroke;
• Baseline NIHSS score ≥ 6 and ≤ 25;
• CTA/MRA/DSA examination suggests large vessel occlusion in the anterior circulation (internal carotid artery, M1/M2 segment of the middle cerebral artery);
• The criteria for receiving endovascular treatment in accordance with the Chinese Guidelines for Early Endovascular Intervention in Acute Ischemic Stroke 2018 and have successful revascularization (TICI ≥ grade 2b);
• Subjects or their legal representatives agree to the treatment and sign the informed consent form.

You may not qualify if:

• Patients with combined posterior circulation infarction;
• The mRS ≥ 2 points before the current episode;
• Patients who are to be treated with or have been treated with anticoagulants;
• Patients with existing or active organ bleeding within 6 months of enrollment, including cerebral hemorrhage, subarachnoid hemorrhage, gastrointestinal tract hemorrhage, fundus hemorrhage, etc;
• The presence of other intracranial pathologies, such as cerebrovascular malformations, cerebral venous lesions, tumors, and other diseases involving the cranium;
• Severe organ dysfunction or failure;
• Those with severe hematologic disorders or severe coagulation abnormalities；
• Those with a history of severe trauma or major surgical procedures within 6 months prior to enrollment;
• Pregnant or lactating women;
• Patients with a life expectancy of less than 3 months or who for other reasons are unable to complete the study;
• Unwillingness to be followed up or poor compliance with treatment;
• Other conditions that the investigator considers unsuitable for enrollment.

Sponsors & Collaborators

• Nanfang Hospital, Southern Medical University: lead

Study Sites (2)

Dongguan Hospital of Southern Medical University

Dongguan, Guangdong, 523059, China

RECRUITING

Nanfang Hospital of Southern Medical University

Guangzhou, Guangdong, 510515, China

RECRUITING

Related Publications (29)

• GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019 May;18(5):439-458. doi: 10.1016/S1474-4422(19)30034-1. Epub 2019 Mar 11.

  PMID: 30871944 BACKGROUND

• Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, Li X, Wang L, Wang L, Liu Y, Liu J, Zhang M, Qi J, Yu S, Afshin A, Gakidou E, Glenn S, Krish VS, Miller-Petrie MK, Mountjoy-Venning WC, Mullany EC, Redford SB, Liu H, Naghavi M, Hay SI, Wang L, Murray CJL, Liang X. Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2019 Sep 28;394(10204):1145-1158. doi: 10.1016/S0140-6736(19)30427-1. Epub 2019 Jun 24.

  PMID: 31248666 BACKGROUND

• Phipps MS, Cronin CA. Management of acute ischemic stroke. BMJ. 2020 Feb 13;368:l6983. doi: 10.1136/bmj.l6983.

  PMID: 32054610 BACKGROUND

• Ma H, Campbell BCV, Parsons MW, Churilov L, Levi CR, Hsu C, Kleinig TJ, Wijeratne T, Curtze S, Dewey HM, Miteff F, Tsai CH, Lee JT, Phan TG, Mahant N, Sun MC, Krause M, Sturm J, Grimley R, Chen CH, Hu CJ, Wong AA, Field D, Sun Y, Barber PA, Sabet A, Jannes J, Jeng JS, Clissold B, Markus R, Lin CH, Lien LM, Bladin CF, Christensen S, Yassi N, Sharma G, Bivard A, Desmond PM, Yan B, Mitchell PJ, Thijs V, Carey L, Meretoja A, Davis SM, Donnan GA; EXTEND Investigators. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019 May 9;380(19):1795-1803. doi: 10.1056/NEJMoa1813046.

  PMID: 31067369 BACKGROUND

• Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, McTaggart RA, Torbey MT, Kim-Tenser M, Leslie-Mazwi T, Sarraj A, Kasner SE, Ansari SA, Yeatts SD, Hamilton S, Mlynash M, Heit JJ, Zaharchuk G, Kim S, Carrozzella J, Palesch YY, Demchuk AM, Bammer R, Lavori PW, Broderick JP, Lansberg MG; DEFUSE 3 Investigators. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018 Feb 22;378(8):708-718. doi: 10.1056/NEJMoa1713973. Epub 2018 Jan 24.

  PMID: 29364767 BACKGROUND

• Patel P, Yavagal D, Khandelwal P. Hyperacute Management of Ischemic Strokes: JACC Focus Seminar. J Am Coll Cardiol. 2020 Apr 21;75(15):1844-1856. doi: 10.1016/j.jacc.2020.03.006.

  PMID: 32299596 BACKGROUND

• Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, Peng Y, Han H, Wang J, Wang S, Yin C, Liu S, Wang P, Fang Q, Shi H, Yang J, Wen C, Li C, Jiang C, Sun J, Yue X, Lou M, Zhang M, Shu H, Sun D, Liang H, Li T, Guo F, Ke K, Yuan H, Wang G, Yang W, Shi H, Li T, Li Z, Xing P, Zhang P, Zhou Y, Wang H, Xu Y, Huang Q, Wu T, Zhao R, Li Q, Fang Y, Wang L, Lu J, Li Y, Fu J, Zhong X, Wang Y, Wang L, Goyal M, Dippel DWJ, Hong B, Deng B, Roos YBWEM, Majoie CBLM, Liu J; DIRECT-MT Investigators. Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke. N Engl J Med. 2020 May 21;382(21):1981-1993. doi: 10.1056/NEJMoa2001123. Epub 2020 May 6.

  PMID: 32374959 BACKGROUND

• Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010 Jul 29;67(2):181-98. doi: 10.1016/j.neuron.2010.07.002.

  PMID: 20670828 BACKGROUND

• Shi K, Zou M, Jia DM, Shi S, Yang X, Liu Q, Dong JF, Sheth KN, Wang X, Shi FD. tPA Mobilizes Immune Cells That Exacerbate Hemorrhagic Transformation in Stroke. Circ Res. 2021 Jan 8;128(1):62-75. doi: 10.1161/CIRCRESAHA.120.317596. Epub 2020 Oct 19.

  PMID: 33070717 BACKGROUND

• Wang R, Zhu Y, Liu Z, Chang L, Bai X, Kang L, Cao Y, Yang X, Yu H, Shi MJ, Hu Y, Fan W, Zhao BQ. Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke. Blood. 2021 Jul 8;138(1):91-103. doi: 10.1182/blood.2020008913.

  PMID: 33881503 BACKGROUND

• El-Benna J, Hurtado-Nedelec M, Marzaioli V, Marie JC, Gougerot-Pocidalo MA, Dang PM. Priming of the neutrophil respiratory burst: role in host defense and inflammation. Immunol Rev. 2016 Sep;273(1):180-93. doi: 10.1111/imr.12447.

  PMID: 27558335 BACKGROUND

• Chen R, Zhang X, Gu L, Zhu H, Zhong Y, Ye Y, Xiong X, Jian Z. New Insight Into Neutrophils: A Potential Therapeutic Target for Cerebral Ischemia. Front Immunol. 2021 Jul 14;12:692061. doi: 10.3389/fimmu.2021.692061. eCollection 2021.

  PMID: 34335600 BACKGROUND

• Jian Z, Liu R, Zhu X, Smerin D, Zhong Y, Gu L, Fang W, Xiong X. The Involvement and Therapy Target of Immune Cells After Ischemic Stroke. Front Immunol. 2019 Sep 11;10:2167. doi: 10.3389/fimmu.2019.02167. eCollection 2019.

  PMID: 31572378 BACKGROUND

• O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006 Mar;59(3):467-77. doi: 10.1002/ana.20741.

  PMID: 16453316 BACKGROUND

• Zhou Z, Lu J, Liu WW, Manaenko A, Hou X, Mei Q, Huang JL, Tang J, Zhang JH, Yao H, Hu Q. Advances in stroke pharmacology. Pharmacol Ther. 2018 Nov;191:23-42. doi: 10.1016/j.pharmthera.2018.05.012. Epub 2018 May 25.

  PMID: 29807056 BACKGROUND

• Elkins J, Veltkamp R, Montaner J, Johnston SC, Singhal AB, Becker K, Lansberg MG, Tang W, Chang I, Muralidharan K, Gheuens S, Mehta L, Elkind MSV. Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol. 2017 Mar;16(3):217-226. doi: 10.1016/S1474-4422(16)30357-X. Epub 2017 Feb 15.

  PMID: 28229893 BACKGROUND

• Nusse R, Clevers H. Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell. 2017 Jun 1;169(6):985-999. doi: 10.1016/j.cell.2017.05.016.

  PMID: 28575679 BACKGROUND

• Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012 Jun 8;149(6):1192-205. doi: 10.1016/j.cell.2012.05.012.

  PMID: 22682243 BACKGROUND

• Routledge D, Scholpp S. Mechanisms of intercellular Wnt transport. Development. 2019 May 15;146(10):dev176073. doi: 10.1242/dev.176073.

  PMID: 31092504 BACKGROUND

• Chang J, Mancuso MR, Maier C, Liang X, Yuki K, Yang L, Kwong JW, Wang J, Rao V, Vallon M, Kosinski C, Zhang JJ, Mah AT, Xu L, Li L, Gholamin S, Reyes TF, Li R, Kuhnert F, Han X, Yuan J, Chiou SH, Brettman AD, Daly L, Corney DC, Cheshier SH, Shortliffe LD, Wu X, Snyder M, Chan P, Giffard RG, Chang HY, Andreasson K, Kuo CJ. Gpr124 is essential for blood-brain barrier integrity in central nervous system disease. Nat Med. 2017 Apr;23(4):450-460. doi: 10.1038/nm.4309. Epub 2017 Mar 13.

  PMID: 28288111 BACKGROUND

• Ji YB, Gao Q, Tan XX, Huang XW, Ma YZ, Fang C, Wang SN, Qiu LH, Cheng YX, Guo FY, Chang J. Lithium alleviates blood-brain barrier breakdown after cerebral ischemia and reperfusion by upregulating endothelial Wnt/beta-catenin signaling in mice. Neuropharmacology. 2021 Mar 15;186:108474. doi: 10.1016/j.neuropharm.2021.108474. Epub 2021 Jan 29.

  PMID: 33524408 BACKGROUND

• Ta S, Rong X, Guo ZN, Jin H, Zhang P, Li F, Li Z, Lin L, Zheng C, Gu Q, Zhang Y, Liu W, Yang Y, Chang J. Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke. CNS Neurosci Ther. 2021 Jan;27(1):71-81. doi: 10.1111/cns.13457. Epub 2020 Sep 29.

  PMID: 32991049 BACKGROUND

• Song D, Zhang X, Chen J, Liu X, Xue J, Zhang L, Lan X. Wnt canonical pathway activator TWS119 drives microglial anti-inflammatory activation and facilitates neurological recovery following experimental stroke. J Neuroinflammation. 2019 Dec 6;16(1):256. doi: 10.1186/s12974-019-1660-8.

  PMID: 31810470 BACKGROUND

• Wei ZZ, Zhang JY, Taylor TM, Gu X, Zhao Y, Wei L. Neuroprotective and regenerative roles of intranasal Wnt-3a administration after focal ischemic stroke in mice. J Cereb Blood Flow Metab. 2018 Mar;38(3):404-421. doi: 10.1177/0271678X17702669. Epub 2017 Apr 21.

  PMID: 28430000 BACKGROUND

• Wang W, Li M, Wang Y, Wang Z, Zhang W, Guan F, Chen Q, Wang J. GSK-3beta as a target for protection against transient cerebral ischemia. Int J Med Sci. 2017 Mar 11;14(4):333-339. doi: 10.7150/ijms.17514. eCollection 2017.

  PMID: 28553165 BACKGROUND

• Wu MV, Hen R. The young and the restless: regulation of adult neurogenesis by Wnt signaling. Cell Stem Cell. 2013 Feb 7;12(2):139-40. doi: 10.1016/j.stem.2013.01.013.

  PMID: 23395437 BACKGROUND

• Busceti CL, Biagioni F, Aronica E, Riozzi B, Storto M, Battaglia G, Giorgi FS, Gradini R, Fornai F, Caricasole A, Nicoletti F, Bruno V. Induction of the Wnt inhibitor, Dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy. Epilepsia. 2007 Apr;48(4):694-705. doi: 10.1111/j.1528-1167.2007.01055.x.

  PMID: 17437412 BACKGROUND

• Cappuccio I, Calderone A, Busceti CL, Biagioni F, Pontarelli F, Bruno V, Storto M, Terstappen GT, Gaviraghi G, Fornai F, Battaglia G, Melchiorri D, Zukin RS, Nicoletti F, Caricasole A. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is required for the development of ischemic neuronal death. J Neurosci. 2005 Mar 9;25(10):2647-57. doi: 10.1523/JNEUROSCI.5230-04.2005.

  PMID: 15758175 BACKGROUND

• Mastroiacovo F, Busceti CL, Biagioni F, Moyanova SG, Meisler MH, Battaglia G, Caricasole A, Bruno V, Nicoletti F. Induction of the Wnt antagonist, Dickkopf-1, contributes to the development of neuronal death in models of brain focal ischemia. J Cereb Blood Flow Metab. 2009 Feb;29(2):264-76. doi: 10.1038/jcbfm.2008.111. Epub 2008 Oct 1.

  PMID: 18827832 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Venous blood samples of acute stroke patients with revascularisation treatment

MeSH Terms

Conditions

Ischemic Stroke; Reperfusion Injury; Brain Edema

Condition Hierarchy (Ancestors)

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Zhu Shi, PHD

  Dongguan Hospital of Southern Medical University

  STUDY CHAIR

Central Study Contacts

Kaibin Huang, PHD

CONTACT

020-62787664; hkb@smu.edu.cn

Zhu Shi, PHD

CONTACT

0769-28636833; sound_shi@126.com

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 90 Days
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: associate chief physician

Study Record Dates

• First Submitted: September 21, 2022
• First Posted: October 18, 2022
• Study Start: September 1, 2022
• Primary Completion: September 30, 2024
• Study Completion: September 30, 2024
• Last Updated: March 25, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

CN (2)