Clinical trial NCT06429384: Y-3 Injection in the Treatment of Acute Ischemic Stroke Phase II Clinical Trial
Official title: Y-3 Injection in the Treatment of Acute Ischemic Stroke Phase II Clinical Trial -- Multicenter, Randomized, Double-blind, Parallel, Placebo-controlled Phase II Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Ischemic Stroke
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
Collaborators: name: Neurodawn Pharmaceutical Co., Ltd.
First posted: 2024-05-28
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Y-3 low dose group (20 mg/ time, qd), medium dose group (40 mg/ time qd), high dose group (60mg/ time, qd) and placebo control group.
Primary purpose: TREATMENT

Brief summary: The objective of this clinical trial was to explore the efficacy and safety of Y-3 injection at different doses in patients with acute ischemic stroke within 48 hours of onset.

A multicenter, randomized, double-blind, parallel, placebo-controlled trial design was designed to include 240 participants.

Subjects press 1:1:1: 1 ratio of patients were randomly divided into Y-3 low-dose group (20 mg/ time, qd), medium-dose group (40 mg/ time, qd), high-dose group (60mg/ time, qd) and placebo control group, with 60 cases in each group. Random stratification factors include:

Time of onset (≤24 hours, \&gt; 24 hours). The patients were treated for 10 consecutive days (10 times) and followed up to 90 days after the first dose.

The trial was divided into three phases: screening/baseline, treatment, and follow-up.

Screening/baseline period: Subjects enter the screening/baseline period for screening examination after signing the informed consent.

Treatment period: Eligible subjects were randomly assigned at a ratio of 1:1:1:1 to receive Y-3 injection low-dose group, medium-dose group, high-dose group and placebo control drug for 10 consecutive days (10 times), during which relevant examinations required by the protocol were conducted and safety was assessed.

Follow-up period: Participants who finished treatment were followed up until 90 days after the first dose.

Stroke-related scale scores were performed at 10, 30, and 90 days after first use of the investigational drug The scores of Montgomery Depression Rating Scale (MSAS) and Hamilton Anxiety Scale (HAMA) were performed on the 10th and 90th days after the use of experimental drugs. Adverse events were recorded during treatment and follow-up to further assess safety

Detailed description: A multicenter, randomized, double-blind, parallel, placebo-controlled trial design was designed to include 240 participants, who were randomly assigned to Y-3 low-dose group (20 mg/ time, qd), medium-dose group (40 mg/ time, qd), high-dose group (60 mg/ time, qd) and placebo control group in a ratio of 1:1:1:1. Each group had 60 cases.

Random stratification factors included: onset time (≤24 hours, \> 24 hours).The patients were treated for 10 consecutive days (10 times) and followed up to 90 days after the first dose.

The trial was divided into three phases:screening/baseline, treatment, and follow-up.

Screening/baseline period: Subjects enter the screening/baseline period for screening examination after signing the informed consent.Treatment period: Eligible subjects were randomly assigned at a ratio of 1:1:1:1 to receive Y-3 injection low-dose group, medium-dose group, high-dose group and placebo control drug for 10 consecutive days (10 times), during which relevant examinations required by the protocol were conducted and safety was assessed.Follow-up period: Participants who finished treatment were followed up until 90 days after the first dose.Stroke-related scale scores were performed on the 10th, 30th and 90th days after the first use of the experimental drug, and Montgomery Depression Rating Scale (MADRS) and Hamilton Anxiety Scale (HAMA) scores were performed on the 10th and 90th days after the first use of the experimental drug. Adverse events were recorded during treatment and follow-up to further assess safety.

Eligibility criteria: Inclusion Criteria:

-

Only those who meet all the following criteria can be included in the group:

1. Age ≥ 18 years old and\<81 years old, regardless of gender;
2. After the onset of this disease, the National Institutes of Research Stroke Scale score was 6 ≤ NIHSS ≤ 20 points, and the sum of the 5th upper limb and 6th lower limb scores was ≥ 2 points. If patients receiving thrombolysis treatment were screened and evaluated based on the NIHSS score after thrombolysis;
3. Within 48 hours (including 48 hours) of onset;
4. Diagnosed as ischemic stroke according to the "Key Diagnostic Points for Various Major Cerebrovascular Diseases in China 2019", with good recovery after the first or last onset (mRS score ≤ 1 point before this onset);
5. Obtain informed consent from the patient or their legal representative voluntarily signed and approved by the ethics committee.

Exclusion Criteria:

-

Those who meet one of the following criteria during filtering cannot be included in the group:

1. Intracranial hemorrhagic diseases seen on cranial imaging: hemorrhagic stroke, epidural hematoma, intracranial hematoma, ventricular hemorrhage, subarachnoid hemorrhage, etc; If it is only oozing blood, the researcher can determine whether it is suitable for enrollment;
2. Severe consciousness disorder: The item score of NIHSS's 1a consciousness level is greater than 1 point;
3. Transient ischemic attack (TIA);
4. After controlling the patient's blood pressure, the systolic blood pressure remains ≥ 220mmHg or the diastolic blood pressure remains ≥ 120mmHg;
5. Previously diagnosed patients with severe mental disorders and severe dementia;
6. Patients previously diagnosed with depression or anxiety disorder;
7. Patients undergoing antidepressant or anti anxiety treatment;
8. Diagnosed with severe active liver diseases, such as acute hepatitis, chronic active hepatitis, liver cirrhosis, etc; Or ALT or AST\>2.0 × ULN;
9. Diagnosed with severe active kidney disease or renal insufficiency; Or serum creatinine\>1.5 × ULN;
10. After the onset of the disease, drugs with brain cytoprotection in the instructions have been used, such as edaravone, concentrated solution of edaravone and dextranol for injection, nimodipine, ganglioside, CDPC, piracetam, oxiracetam, butylphenylpeptide, human urinary kallidinogenase (Urinary Kallidinogenase), cinepazide, rat nerve growth factor, cerebrolysin (cerebroprotein hydrolysate), calf serum deproteinized injection Calf blood deproteinized extract injection, etc;
11. After the onset of this disease, thrombectomy or interventional therapy has been applied or planned to be applied;
12. Previously diagnosed with concurrent malignant tumors and undergoing anti-tumor treatment;
13. Previously diagnosed with severe systemic diseases, with an estimated survival period of\<90 days;
14. The patient is in pregnancy, lactation, and there is a possibility of pregnancy in the patient/patient partner who plans to conceive during the trial period;
15. Previously known allergies to this product or any of its excipients (15-hydroxystearic acid polyethylene glycol ester, propylene glycol, sodium hydroxide);
16. A history of major surgeries within 4 weeks prior to enrollment and assessed by the researcher as affecting neurological function scores or affecting 90 day survival;
17. Have participated in other clinical studies or are currently participating in other clinical studies within the first 30 days of randomization;
18. The researcher believes that it is not suitable to participate in this clinical study.

Primary outcomes:
measure: The proportion of subjects with mRS score ≤ 1 on the 90th day of treatment .
timeFrame: 90th day of treatment
Secondary outcomes:
measure: Grade analysis of mRS Score on the 90th day of treatment;
timeFrame: 90th day of treatment
measure: The proportion of subjects with mRS Score ≤2 on the 90th day of treatment;
timeFrame: 90th day of treatment
measure: Changes in NIH Stroke Scale from baseline on day 10 of treatment;
timeFrame: 10th day of treatment
measure: Proportion of NIH Stroke of 0-1 or ≥4 reduction from baseline on day 10 and day 30 of treatment.
timeFrame: On the 10th and 30th day of treatment
Other outcomes:
measure: Montgomery Depression Rating Scale scores on day 10 and day 90 were &lt, respectively; Proportion of patients with scores of 12, ≥12, and ≥22;
timeFrame: On the 10th and 90th day of treatment
measure: Hamilton Anxiety Scale scores on day 10 and day 90 were &lt, respectively; Proportion of patients with scores of 7, ≥7, and ≥14.
timeFrame: On the 10th and 90th day of treatment
measure: Incidence of adverse events (AE) in each group;
timeFrame: From the time the subject receives medication to the end of the 90th day of the treatment
measure: The incidence of treatment-related adverse events (TEAEs) in each group;
timeFrame: From the time the subject receives medication to the end of the 90th day of the treatment
measure: The occurrence of important adverse events in each group;
timeFrame: From the time the subject receives medication to the end of the 90th day of the treatment
measure: The occurrence of serious adverse events (SAEs) in each group;
timeFrame: From the time the subject receives medication to the end of the 90th day of the treatment
measure: The occurrence of suspicious and unexpected serious adverse reactions (SUSAR) in each group;
timeFrame: From the time the subject receives medication to the end of the 90th day of the treatment
measure: Laboratory examination indicators: blood routine, urine routine, blood biochemistry, Laboratory examination indicators: blood routine, urine routine, blood biochemistry, coagulation function
timeFrame: Baseline period, on the 10th , 30th and 90th day
measure: Vital signs: heart rate, blood pressure, body temperature, respiration
timeFrame: Baseline period, on the 10th , 30th and 90th day
measure: Physical examination of the whole body: lungs, gastrointestinal tract, urinary system, musculoskeletal system, skin, lymph nodes, and other systems.
timeFrame: Baseline period, on the 10th , 30th and 90th day
measure: Clinical laboratory examination
timeFrame: From the baseline period to the end of the 90th day of the treatment
measure: Discontinuation due to adverse events;
timeFrame: From the beginning to the end caused by adverse events
measure: Discontinuation due to any other non-adverse event.
timeFrame: From the beginning to the end due to unexpected circumstances except for adverse events
Locations:
city: Beijing
country: China
facility: Beijing Tiantan Hospital, Capital Medical University Beijing
state: Beijing
city: Liuzhou
country: China
facility: Liuzhou Workers Hospital
state: Guangxi
city: Cangzhou
country: China
facility: Cangzhou Central Hospital
state: Hebei
city: Hengshui
country: China
facility: Harrison International Peace Hospital
state: Hebei
city: Daqing
country: China
facility: Daqing Oilfield General Hospital
state: Heilongjiang
city: Daqing
country: China
facility: Daqing People's Hospital
state: Heilongjiang
city: Nanyang
country: China
facility: Nanyang Second People's Hospital
state: Henan
city: Nanyang
country: China
facility: Nanyang South Stone Hospital
state: Henan
city: Nanyang
country: China
facility: The First Affiliated Hospital of Nanyang Medical College
state: Henan
city: Changsha
country: China
facility: Hunan Provincial People's Hospital
state: Hunan
city: Baotou
country: China
facility: The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology
state: Inner Mongolia Autonomous Region
city: Baotou
country: China
facility: Inner Mongolia Baotou Steel Hospital
state: Inner Mongolia Autonomous Region
city: Hohhot
country: China
facility: Inner Mongolia International Mongolian Medicine Hospital
state: Inner Mongolia Autonomous Region
city: Huai'an
country: China
facility: Huai 'an First People's Hospital
state: Jiangsu
city: Lianyungang
country: China
facility: Lianyungang First People's Hospital
state: Jiangsu
city: Lianyungang
country: China
facility: Lianyungang Second People's Hospital
state: Jiangsu
city: Taizhou
country: China
facility: Taizhou Second People's Hospital
state: Jiangsu
city: Xuzhou
country: China
facility: Xuzhou Central Hospital (Old Hospital Area)
state: Jiangsu
city: Xuzhou
country: China
facility: Xuzhou Central Hospital（New compound）
state: Jiangsu
city: Xuzhou
country: China
facility: Xuzhou First People's Hospital
state: Jiangsu
city: Pingxiang
country: China
facility: Pingxiang People's Hospital
state: Jiangxi
city: Beipiao
country: China
facility: Beipiao Central Hospital
state: Liaoning
city: Jinzhou
country: China
facility: The First Affiliated Hospital of Jinzhou Medical University
state: Liaoning
city: Shenyang
country: China
facility: Chinese People's Liberation Army Northern Theater Command General Hospital
state: Liaoning
city: Shenyang
country: China
facility: Shenyang First People's Hospital
state: Liaoning
city: Jinan
country: China
facility: Shandong Third Hospital
state: Shandong
city: Liaocheng
country: China
facility: Liaocheng People's Hospital
state: Shandong
city: Linyi
country: China
facility: Tancheng County First People's Hospital
state: Shandong
city: Tengzhou
country: China
facility: Tengzhou Central People's Hospital
state: Shandong
city: Dongyang
country: China
facility: Dongyang City People's Hospital
state: Zhejiang
Study officials:
affiliation: IRB of Beijing Tiantan Hospital Capital Medical University Beijing
name: Shuya Li
role: STUDY_DIRECTOR
References:
citation: Smith WS, Lev MH, English JD, Camargo EC, Chou M, Johnston SC, Gonzalez G, Schaefer PW, Dillon WP, Koroshetz WJ, Furie KL. Significance of large vessel intracranial occlusion causing acute ischemic stroke and TIA. Stroke. 2009 Dec;40(12):3834-40. doi: 10.1161/STROKEAHA.109.561787. Epub 2009 Oct 15.
citation: Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, Brott T, Cohen G, Davis S, Donnan G, Grotta J, Howard G, Kaste M, Koga M, von Kummer R, Lansberg M, Lindley RI, Murray G, Olivot JM, Parsons M, Tilley B, Toni D, Toyoda K, Wahlgren N, Wardlaw J, Whiteley W, del Zoppo GJ, Baigent C, Sandercock P, Hacke W; Stroke Thrombolysis Trialists' Collaborative Group. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014 Nov 29;384(9958):1929-35. doi: 10.1016/S0140-6736(14)60584-5. Epub 2014 Aug 5.
citation: Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019 Dec;50(12):e344-e418. doi: 10.1161/STR.0000000000000211. Epub 2019 Oct 30.
citation: Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL; American Heart Association Stroke Council. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018 Mar;49(3):e46-e110. doi: 10.1161/STR.0000000000000158. Epub 2018 Jan 24.
citation: van Horn N, Kniep H, Leischner H, McDonough R, Deb-Chatterji M, Broocks G, Thomalla G, Brekenfeld C, Fiehler J, Hanning U, Flottmann F. Predictors of poor clinical outcome despite complete reperfusion in acute ischemic stroke patients. J Neurointerv Surg. 2021 Jan;13(1):14-18. doi: 10.1136/neurintsurg-2020-015889. Epub 2020 May 15.
citation: Lee SH, Kim BJ, Han MK, Park TH, Lee KB, Lee BC, Yu KH, Oh MS, Cha JK, Kim DH, Nah HW, Lee J, Lee SJ, Kim JG, Park JM, Kang K, Cho YJ, Hong KS, Park HK, Choi JC, Kim JT, Choi K, Kim DE, Ryu WS, Kim WJ, Shin DI, Yeo M, Sohn SI, Hong JH, Lee J, Lee JS, Khatri P, Bae HJ. Futile reperfusion and predicted therapeutic benefits after successful endovascular treatment according to initial stroke severity. BMC Neurol. 2019 Jan 15;19(1):11. doi: 10.1186/s12883-019-1237-2.
citation: Meyer L, Alexandrou M, Leischner H, Flottmann F, Deb-Chatterji M, Abdullayev N, Maus V, Politi M, Roth C, Kastrup A, Thomalla G, Mpotsaris A, Fiehler J, Papanagiotou P. Mechanical thrombectomy in nonagenarians with acute ischemic stroke. J Neurointerv Surg. 2019 Nov;11(11):1091-1094. doi: 10.1136/neurintsurg-2019-014785. Epub 2019 Apr 27.
citation: Chamorro A, Lo EH, Renu A, van Leyen K, Lyden PD. The future of neuroprotection in stroke. J Neurol Neurosurg Psychiatry. 2021 Feb;92(2):129-135. doi: 10.1136/jnnp-2020-324283. Epub 2020 Nov 4.
citation: Li J, Zhang L, Xu C, Shen YY, Lin YH, Zhang Y, Wu HY, Chang L, Zhang YD, Chen R, Zhang ZP, Luo CX, Li F, Zhu DY. A pain killer without analgesic tolerance designed by co-targeting PSD-95-nNOS interaction and alpha2-containning GABAARs. Theranostics. 2021 Apr 3;11(12):5970-5985. doi: 10.7150/thno.58364. eCollection 2021.
citation: Li J, Zhang L, Xu C, Lin YH, Zhang Y, Wu HY, Chang L, Zhang YD, Luo CX, Li F, Zhu DY. Prolonged Use of NMDAR Antagonist Develops Analgesic Tolerance in Neuropathic Pain via Nitric Oxide Reduction-Induced GABAergic Disinhibition. Neurotherapeutics. 2020 Jul;17(3):1016-1030. doi: 10.1007/s13311-020-00883-w.
citation: Kaur H, Prakash A, Medhi B. Drug therapy in stroke: from preclinical to clinical studies. Pharmacology. 2013;92(5-6):324-34. doi: 10.1159/000356320. Epub 2013 Dec 12.
citation: Fisher M; Stroke Therapy Academic Industry Roundtable. Recommendations for advancing development of acute stroke therapies: Stroke Therapy Academic Industry Roundtable 3. Stroke. 2003 Jun;34(6):1539-46. doi: 10.1161/01.STR.0000072983.64326.53. Epub 2003 May 15.
citation: Hackett ML, Kohler S, O'Brien JT, Mead GE. Neuropsychiatric outcomes of stroke. Lancet Neurol. 2014 May;13(5):525-34. doi: 10.1016/S1474-4422(14)70016-X. Epub 2014 Mar 28.
citation: Ferro JM, Caeiro L, Figueira ML. Neuropsychiatric sequelae of stroke. Nat Rev Neurol. 2016 May;12(5):269-80. doi: 10.1038/nrneurol.2016.46. Epub 2016 Apr 11.
citation: Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017 Jul;16(7):472-486. doi: 10.1038/nrd.2017.16. Epub 2017 Mar 17.
citation: Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry. 2011 Apr;16(4):383-406. doi: 10.1038/mp.2010.120. Epub 2010 Nov 16.
citation: Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009 Oct 16;139(2):267-84. doi: 10.1016/j.cell.2009.09.028.
citation: Griebel G, Holmes A. 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov. 2013 Sep;12(9):667-87. doi: 10.1038/nrd4075.
citation: Shabel SJ, Proulx CD, Piriz J, Malinow R. Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment. Science. 2014 Sep 19;345(6203):1494-8. doi: 10.1126/science.1250469. Epub 2014 Sep 18.
citation: Li YF. A hypothesis of monoamine (5-HT) - Glutamate/GABA long neural circuit: Aiming for fast-onset antidepressant discovery. Pharmacol Ther. 2020 Apr;208:107494. doi: 10.1016/j.pharmthera.2020.107494. Epub 2020 Jan 25.
citation: Gould TD, Zarate CA Jr, Thompson SM. Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants. Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:213-236. doi: 10.1146/annurev-pharmtox-010617-052811. Epub 2018 Oct 8.
citation: Zhou L, Li F, Xu HB, Luo CX, Wu HY, Zhu MM, Lu W, Ji X, Zhou QG, Zhu DY. Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95. Nat Med. 2010 Dec;16(12):1439-43. doi: 10.1038/nm.2245. Epub 2010 Nov 21.
citation: Luo CX, Lin YH, Qian XD, Tang Y, Zhou HH, Jin X, Ni HY, Zhang FY, Qin C, Li F, Zhang Y, Wu HY, Chang L, Zhu DY. Interaction of nNOS with PSD-95 negatively controls regenerative repair after stroke. J Neurosci. 2014 Oct 1;34(40):13535-48. doi: 10.1523/JNEUROSCI.1305-14.2014.