A randomized, double-blind, placebo-controlled, multicenter trial- DL-3-n-butylphthalide therapy for cerebral hypoperfusion from unilateral internal carotid system stenosis study: study protocol

Authors

  • Dawei Chen Department of Neurology, Air Force Medical Center, Chinese PLA, Beijing, China
  • Yanwei Yin Department of Neurology, Air Force Medical Center, Chinese PLA, Beijing, China
  • Jin Shi Department of Neurology, Air Force Medical Center, Chinese PLA, Beijing, China
  • Xiaoxuan Ma Department of Radiology, Air Force Medical Center, Chinese PLA, Beijing, China
  • Huiping Shi Department of Radiology, Air Force Medical Center, Chinese PLA, Beijing, China
  • Feng Huang Department of Medical Statistics, Air Force Medical Center, Chinese PLA, Beijing, China
  • Feng Qiu Department of Neurology, The Eighth Medical Center, Chinese PLA General Hospital, Beijing, China
  • Yonghong Tang Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South, Hunan, China

DOI:

https://doi.org/10.18203/2349-3259.ijct20230052

Keywords:

DL-3-n-butylphthalide, Cerebral large-vessel stenosis, Cerebral hypoperfusion, Computed tomography perfusion, Randomized double-blind controlled trial

Abstract

Background: Cerebral hypoperfusion caused by large-vessel stenosis is an important risk factor for ischemic stroke and vascular cognitive impairment. In vitro, animal and clinic studies demonstrated that DL-3-n-butylphthalide (NBP) can improve the collateral circulation and the cerebral perfusion. In this trial, the benefit of NBP to ameliorate the chronic cerebral hypoperfusion resulting from unilateral internal carotid system stenosis will be explored.

Methods: This trial is a randomized, double-blind, placebo-controlled, multicenter clinical study. A total 480 subjects with ≥70% stenosis or occlusion in unilateral internal carotid artery system, cerebral hypoperfusion in the ipsilateral middle cerebral artery (MCA) territory, and no transient ischemic attacks (TIA) or ischemic strokes within 2 weeks will be enrolled in China. Patients will be assigned in a 1:1 ratio to NBP and placebo groups. Patients in NBP or placebo group received 200 mg or 20 mg of NBP capsules three times daily for 4 weeks respectively. The cerebral perfusion will be assessed again after 12 weeks. The primary efficacy outcome is the proportion of patients with cerebral blood flow (CBF) amelioration, stabilization and deterioration after treatment.

Conclusions: This trial will provide a high-level of evidence for NBP to treat the cerebral hypoperfusion, and a novel strategy to improve the cerebral hemodynamic impairment due to large intracranial and extracranial atherosclerotic stenosis in the surgical high-risk patients, especially in the aged and Asians.

Trial registration: This trial is registered as ChiCTR2100053112 on November 12th, 2021.

References

Banerjee C, Turan TN. Large Artery Atherosclerosis: Extracranial and Intracranial. Semin Neurol. 2017;37(3):307-15.

Naylor AR, Ricco JB, de Borst GJ, Debus S, de Haro J, Halliday A, et al. Editor's Choice-Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg. 2018; 55(1):3-81.

Eckstein HH, Kühnl A, Berkefeld J, Lawall H, Storck M, Sander D. Diagnosis, treatment and follow-up in extracranial carotid stenosis. Dtsch Arztebl Int. 2020;117(47):801-7.

Cheng SF, Brown MM, Simister RJ, Richards T. Contemporary prevalence of carotid stenosis in patients presenting with ischaemic stroke. Br J Surg. 2019;106(7):872-8.

Derdeyn CP, Chimowitz MI, Lynn MJ, Fiorella D, Turan TN, Janis LS, et al. Aggressive Medical Treatment With or Without Stenting in High-Risk Patients With Intracranial Artery Stenosis (SAMMPRIS): The Final Results of a Randomised Trial. Lancet 2014;383(9914):333-41.

Zaidat OO, Fitzsimmons BF, Woodward BK, Wang Z, Killer-Oberpfalzer M, Wakhloo A, et al. Effect of a balloon-expandable intracranial stent vs medical therapy on risk of stroke in patients with symptomatic intracranial stenosis: the VISSIT randomized clinical trial. JAMA. 2015;313:1240-8.

Liu D, Liu J, Cai Y, Wong KSL, Liu L. Is the future of symptomatic intracranial atherosclerotic stenosis management promising? J Neurol Neurosurg Psychiatry. 2020;91(2):122-4.

Ginsberg MD. The cerebral collateral circulation: Relevance to pathophysiology and treatment of stroke. Neuropharmacology. 2018;134(Pt B):280-92.

Liu L, Ding J, Leng X, Pu Y, Huang LA, Xu A, et al. Guidelines for evaluation and management of cerebral collateral circulation in ischaemic stroke 2017. Stroke Vasc Neurol. 2018;30;3(3):117-30.

Liebeskind DS, Cotsonis GA, Saver JL, Lynn MJ, Turan TN, Cloft HJ, et al. Collaterals dramatically alter stroke risk in intracranial atherosclerosis. Ann Neurol. 2011;69(6):963-74.

Wabnitz AM, Derdeyn CP, Fiorella DJ, Lynn MJ, Cotsonis GA, Liebeskind DS, et al. SAMMPRIS Investigators. Hemodynamic Markers in the Anterior Circulation as Predictors of Recurrent Stroke in Patients with Intracranial Stenosis. Stroke. 2018;1.

Wang S, Ma F, Huang L, Zhang Y, Peng Y, Xing C, et al. Dl-3-n-Butylphthalide (NBP): A Promising Therapeutic Agent for Ischemic Stroke. CNS Neurol Disord Drug Targets. 2018;17(5):338-47.

Wei ZZ, Chen D, Lee MJH, Zhao Y, Gu X, Yu SP, et al. DL-3-n-butylphthalide Increases Collateriogenesis and Functional Recovery after Focal Ischemic Stroke in Mice. Aging Dis. 2021;12(7):1835-49.

Wang J, Li Y, Yu H, Li G, Bai S, Chen S, et al. Dl-3-N-Butylphthalide Promotes Angiogenesis in an Optimized Model of Transient Ischemic Attack in C57BL/6 Mice. Front Pharmacol. 2021;2:751397.

Niu X, Li M, Gao Y, Xu G, Dong X, Chu B, et al. DL-3-n-butylphthalide suppressed autophagy and promoted angiogenesis in rats with vascular dementia by activating the Shh/Ptch1 signaling pathway. Neurosci Lett. 2021;765:136266.

Xiong Z, Lu W, Zhu L, Zeng L, Shi C, Jing Z, et al. Dl-3-n-Butylphthalide Treatment Enhances Hemodynamics and Ameliorates Memory Deficits in Rats with Chronic Cerebral Hypoperfusion. Front Aging Neurosci. 2017;9:238.

Han QY, Zhang H, Zhang X, He DS, Wang SW, Cao X, et al. dl-3-n-butylphthalide preserves white matter integrity and alleviates cognitive impairment in mice with chronic cerebral hypoperfusion. CNS Neurosci Ther. 2019;25(9):1042-53.

Yu-Fu W, Xiao-Hong L, Wei-Cheng G, Jie Z, Hao-Ran W, Fei-Fei H. Effect. Observation of Butylphthalide Injection in Treating Acute Anterior Circulation Infarction. Chin J Stroke. 2017;12(12):1111-4.

Zhao H, Yun W, Zhang Q, Cai X, Li X, Hui G, et al. Mobilization of circulating endothelial progenitor cells by dl-3-n-butylphthalide in acute ischemic stroke patients. J Stroke Cerebrovasc Dis. 2016;25:752-60.

Chen D, Yin Y, Shi J, Yang F, Wang K, Zhao F, et al. DL-3-n-butylphthalide improves cerebral hypoperfusion in patients with large cerebral atherosclerotic stenosis: a singlecenter, randomized, double-blind, placebocontrolled study. BMC Neurol. 2020;20(1):212.

Krishnan P, Murphy A, Aviv RI. CT-based Techniques for Brain Perfusion. Top Magn Reson Imaging. 2017;26(3):113-9.

Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J, Lombardi-Hill D, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2021;52(7):e364-e467.

Kim HJ, Kim TW, Ryu SY, Yang PS, Kwon MJ, Kim JC, et al. Acetazolamide-challenged perfusion magnetic resonance imaging for assessment of cerebrovascular reserve capacity in patients with symptomatic middle cerebral artery stenosis: comparison with technetium-99m-hexamethylpropyleneamine oxime single-photon emission computed tomography. Clin Imaging. 2011;35(6):413-20.

Lanzman B, Heit JJ. Advanced MRI measures of cerebral perfusion and their clinical applications. Top Magn Reson Imaging. 2017;26(2):83-90.

Chen DW, Zheng J, Shi J, Yin YW, Song C, Yang F, et al. Assessment of the Cerebral Hemodynamic Benefits of Carotid Artery Stenting for Patients with Preoperative Hemodynamic Impairment Using Cerebral Single Photon Emission Computed Tomography (SPECT) and Carbon Dioxide Inhalation. Med Sci Monit. 2018;24:5398-404.

Ho ML. Arterial spin labeling: clinical applications. J Neuroradiol. 2018;45(5):276-89.

Waaijer A, Schaaf IC, Velthuis BK, Quist M, Osch MJ, Vonken EPV, et al. Reproducibility of Quantitative CT Brain Perfusion Measurements in Patients with Symptomatic Unilateral Carotid Artery Stenosis. AJNR Am J Neuroradiol. 2007;28(5):927-32.

Waaijer A, Leeuwen MS, Van Osch MJ, Van der Worp BH, Moll FL, Lo RT, et al. Changes in Cerebral Perfusion After Revascularization of Symptomatic Carotid Artery Stenosis: CT Measurement. Radiology. 2007;245(2):541-8.

Song P, Fang Z, Wang H, Cai Y, Rahimi K, Zhu Y, et al. Global and regional prevalence, burden, and risk factors for carotid atherosclerosis: a systematic review, meta-analysis, and modelling study. Lancet Glob Health. 2020;8(5):e721-9.

Lal BK, Meschia JF, Brott TG, Jones M, Aronow HD, Lackey A, et al. Race differences in high-grade carotid artery stenosis. Stroke. 2021;52(6):2053-9.

Hurford R, Wolters FJ, Li L, Lau KK, Küker W, Rothwell PM. Oxford Vascular Study Phenotyped Cohort. Prevalence, predictors, and prognosis of symptomatic intracranial stenosis in patients with transient ischaemic attack or minor stroke: a population-based cohort study. Lancet Neurol. 2020;19(5):413-21.

Kim JS, Kim YJ, Ahn SH, Kim BJ. Location of cerebral atherosclerosis: Why is there a difference between East and West? Int J Stroke. 2018;13(1):35-46.

Padalia A, Sambursky JA, Skinner C, Moureiden M. Percutaneous Transluminal Angioplasty with Stent Placement versus Best Medical Therapy Alone in Symptomatic Intracranial Arterial Stenosis: A Best Evidence Rev. Cureus. 2018;10(7):e2988.

Wang J, Guo X, Lu W, Liu J, Zhang H, Quan Q, et al. Donepezil Combined with DL-3-n-Butylphthalide Delays Cognitive Decline in Patients with Mild to Moderate Alzheimer's Disease: A Multicenter, Prospective Cohort Study. Alzheimers Dis. 2021;80(2):673-81.

Tan Z, Zhao Y, Yang W, He S, Ding Y, Xu A. Efficacy and Safety of Adherence to dl-3-n-Butylphthalide Treatment in Patients with Non-disabling Minor Stroke and TIA-Analysis from a Nationwide, Multicenter Registry. Front Neurol. 2021;12:720664.

Jia J, Wei C, Liang J, Zhou A, Zuo X, Song H, et al. The effects of DL-3-n-butylphthalide in patients with vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease: A multicentre, randomized, double-blind, placebo-controlled trial. Alzheimers Dement. 2016;12(2):89-99.

Downloads

Published

2023-01-23