Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events(TRACE)

Acute Ischemic Stroke Clinical Trial

Official title:

Phase II Dose-finding Open Study of Recombinant Human TNK Tissue-type Plasminogen Activator (rhTNK-tPA) Injection Administered Within 3 Hours After Onset of Hyperacute Ischemic Stroke

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04676659
• Other study ID #: MK02-2016-01
• Status: Completed
• Phase: Phase 2
• Start date: May 12, 2018
• Est. completion date: July 10, 2020

Study information

• Verified date: December 2020
• Source: Beijing Tiantan Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To explore the safe and efficacious dose of rhTNK-tPA injection administered within 3 hours after onset of hyperacute ischemic stroke; to provide dose evidence for phase III clinical trial.

Description:

To evaluate the safety and efficacy of rhTNK-tPA at different doses of 0.10 mg/kg, 0.25 mg/kg and 0.32 mg/kg compared with standard rt-PA intravenous thrombolytic therapy within 3 hours after onset of ischemic stroke. The primary objective of this study is to evaluate the differences of NIHSS scores among the four treatment groups at 14 days after intravenous thrombolysis.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 240
• Est. completion date: July 10, 2020
• Est. primary completion date: May 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age over 18 years.

2. Time from onset to treatment < 3 hours; the time symptoms start is defined as "the last moment they appear normal".

3. Diagnosis of ischemic stroke according to "2014 China Guideline for Diagnosis and Treatment of Acute Ischemic Stroke" with assessable neurological impairment e.g., language, motor function, cognitive impairment, gaze impairment, visual field deficit and/or visual neglect. Ischemic stroke is defined as sudden acute focal neurological impairment with suspected cerebral ischemia, hemorrhage ruled out by CT scan.

4. mRS > 2 at the first onset or prior onset.

5. Baseline NIHSS score is > 4 and < 26.

6. Signed informed consent.

Exclusion Criteria:

1. Absolute contraindications:

1.1 History of severe head trauma or stroke within 3 months; 1.2 Suspected subarachnoid hemorrhage; 1.3 Arterial puncture at a non-compressible site within the previous 1week; 1.4 History of intracranial hemorrhage; 1.5 Intracranial tumor, vascular malformation, or arterial aneurysm; 1.6 Recent intracranial or intraspinal surgery; 1.7 Systolic blood pressure ? 180 mm Hg, or diastolic blood pressure ? 100 mm Hg; Increased blood pressure; 1.8 Active internal bleeding ; 1.9 Acute bleeding tendency, including platelet count below 100×109/L or otherwise; 1.10 Heparin treatment was performed within 48 h ( APTT exceeded the upper limit of normal range ) ; 1.11 Warfarin has been taken orally , and the international standardized ratio is INR > 1.7 or PT > 15 s ; 1.12 Anticoagulant drugs such as thrombin inhibitor or Xa factor inhibitor , argatroban ( including new anticoagulants with unclear mechanism ) are currently being used , and various sensitive laboratory tests are abnormal ( such as live ) APTT , INR , Platelet count , Serpentine ECT of pulse enzyme setting time ; thrombin time TT or appropriate determination of Xa factor activity ) ; 1.13 Blood glucose < 2.7 mmol/L; 1.14 CT showed multilobular infarction ( low density > 1 / 3 cerebral hemisphere )

2. Relative contraindications : The risks and benefits of thrombolysis should be carefully considered and weighed in the following cases ( that is , although there is one or more relative contraindications , it is not absolutely impossible to thrombolysis ).

2.1 Mild stroke or stroke with rapid improvement of symptoms; 2.2 Women in pregnancy ; 2.3 Symptoms of neurological impairment after seizures ; 2.4 There have been major surgical operations or serious injuries in the last 2 weeks; 2.5 There were gastrointestinal or urinary system bleeding in recent 3 weeks ; 2.6 History of myocardial infarction within 3 months.

3. Have been enrolled in rhTNK-tPA in pre-study or participated in other clinical trials within 3 months prior to screening.

4. Lactating women, or childbearing women who do not use effective contraception.

5. Known allergy to rhTNK-tPA and/or rt-PA or relevant excipients.

6. The researchers judged that not suitable to participate in this study or participate in this study may lead to greater risk for patients ;

7. Can not comply with the test program or follow-up requirements .

Related Conditions & MeSH terms

• Acute Ischemic Stroke
• Ischemia
• Stroke

Intervention

Drug:
• TNK-tPA
Experimental arms for low, middle, and high dosing; and active control arm for the standard protocol

Locations

Country	Name	City	State
China	Baotou Central Hospital	Baotou	Inner Mongolia
China	Inner Mongolia BaoGang Hospital	Baotou	Inner Mongolia
China	Beijing Tiantan Hospital, Capital Medical University	Beijing	Beijing
China	First Hospital of Jilin University	Chang chun	Jilin
China	ChangSha 1st Municipal Hospital	Changsha	Hunan
China	SiChuan University HuaXi Hospital	Chengdu	Sichuan
China	The Ninth People's Hospital of Chongqing	Chongqing	Chongqing
China	First Affiliated Hospital of Jinan University	Guangzhou	Guangdong
China	Affiliated Hosptial to GuiZhou Medical University	Guiyang	Guizhou
China	HaiNan Provincial People's Hospital	Haikou	Hainan
China	Huai'an Second People's Hospital	Huai'an	Jiangsu
China	Linyi People's Hospital	Linyi	Shandong
China	Luoyang First People's Hosptical	Luoyang	Henan
China	The First Hospital Of Qiqihar	Qiqihar	Heilongjiang
China	HuaShan Hospital Affiliated to FuDan University	Shanghai	Shanghai
China	ZhongShan Hospital ,FuDan University	Shanghai	Shanghai
China	First People 's Hospital Of Shenyang	Shenyang	Liaoning
China	General Hospital of Northern War Zone , PLA	Shenyang	Liaoning
China	ShenZhen Hospital ,Beijing University	Shenzhen	Guangdong
China	Hebei Medical University Third Hospital	Shijiazhuang	Hebei
China	Tangshan Workers' Hospital	Tangshan	Hebei
China	Meihekou Central Hospital	Tonghua	Jilin
China	Yantai Yuhuangding Hospital	Yantai	Shandong
China	1st Hospital Affiliated to Zhengzhou University	Zhengzhou	Henan

Sponsors (14)

Lead Sponsor

Collaborator

Beijing Tiantan Hospital

Baotou Central Hospital, First Affiliated Hospital of Jinan University, First Hospital of Jilin University, Fudan University, Guangzhou Recomgen Biotech Co., Ltd., Hebei Medical University Third Hospital, Huashan Hospital, Inner Mongolia Baogang Hospital, Linyi People's Hospital, The First Affiliated Hospital of Zhengzhou University, The First Hospital Of Qiqihar, West China Hospital, Yantai Yuhuangding Hospital

Country where clinical trial is conducted

China, 

References & Publications (18)

Bandera E, Botteri M, Minelli C, Sutton A, Abrams KR, Latronico N. Cerebral blood flow threshold of ischemic penumbra and infarct core in acute ischemic stroke: a systematic review. Stroke. 2006 May;37(5):1334-9. Epub 2006 Mar 30. Review. — View Citation

Carlos A Monlina,Marc Ribo,Marta Rubiera,et al.TNK Induces Faster MCA Recanalization and Leads to Better Short- and Long-term Clinical Outcome Than Native tPA.The TNK-tPA Reperfusion Stroke Study.Stroke2008,39:527 Abstract141.

CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet. 1997 Jun 7;349(9066):1641-9. — View Citation

Coutts SB, Dubuc V, Mandzia J, Kenney C, Demchuk AM, Smith EE, Subramaniam S, Goyal M, Patil S, Menon BK, Barber PA, Dowlatshahi D, Field T, Asdaghi N, Camden MC, Hill MD; TEMPO-1 Investigators. Tenecteplase-tissue-type plasminogen activator evaluation fo — View Citation

Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, Barber PA, Bladin C, De Silva DA, Byrnes G, Chalk JB, Fink JN, Kimber TE, Schultz D, Hand PJ, Frayne J, Hankey G, Muir K, Gerraty R, Tress BM, Desmond PM; EPITHET investigators. Effects of al — View Citation

Davydov L, Cheng JW. Tenecteplase: a review. Clin Ther. 2001 Jul;23(7):982-97; discussion 981. Review. — View Citation

Donnan GA, Baron JC, Ma H, Davis SM. Penumbral selection of patients for trials of acute stroke therapy. Lancet Neurol. 2009 Mar;8(3):261-9. doi: 10.1016/S1474-4422(09)70041-9. Review. — View Citation

Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J M — View Citation

Haley EC Jr, Lyden PD, Johnston KC, Hemmen TM; TNK in Stroke Investigators. A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke. Stroke. 2005 Mar;36(3):607-12. Epub 2005 Feb 3. — View Citation

Haley EC Jr, Thompson JL, Grotta JC, Lyden PD, Hemmen TG, Brown DL, Fanale C, Libman R, Kwiatkowski TG, Llinas RH, Levine SR, Johnston KC, Buchsbaum R, Levy G, Levin B; Tenecteplase in Stroke Investigators. Phase IIB/III trial of tenecteplase in acute isc — View Citation

Huang X, Cheripelli BK, Lloyd SM, Kalladka D, Moreton FC, Siddiqui A, Ford I, Muir KW. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study. Lancet Neurol. 2015 Apr;14(4) — View Citation

Lees GJ. Pharmacology of AMPA/kainate receptor ligands and their therapeutic potential in neurological and psychiatric disorders. Drugs. 2000 Jan;59(1):33-78. Review. — View Citation

Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, Albers GW, Kaste M, Marler JR, Hamilton SA, Tilley BC, Davis SM, Donnan GA, Hacke W; ECASS, ATLANTIS, NINDS and EPITHET rt-PA Study Group, Allen K, Mau J, Meier D, del Zoppo G, De Silva DA, Bu — View Citation

Macleod MR, Petersson J, Norrving B, Hacke W, Dirnagl U, Wagner M, Schwab S; European Hypothermia Stroke Research Workshop. Hypothermia for Stroke: call to action 2010. Int J Stroke. 2010 Dec;5(6):489-92. — View Citation

Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, O'Brien B, Bladin C, McElduff P, Allen C, Bateman G, Donnan G, Davis S, Levi C. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012 Mar 22;366(12): — View Citation

Wahlgren N, Ahmed N, Dávalos A, Hacke W, Millán M, Muir K, Roine RO, Toni D, Lees KR; SITS investigators. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet. 2008 Oct 11;372(9646):1303-9. doi: 10.1 — View Citation

Wang Z, Li J, Wang C, Yao X, Zhao X, Wang Y, Li H, Liu G, Wang A, Wang Y. Gender differences in 1-year clinical characteristics and outcomes after stroke: results from the China National Stroke Registry. PLoS One. 2013;8(2):e56459. doi: 10.1371/journal.po — View Citation

Wei JW, Heeley EL, Wang JG, Huang Y, Wong LK, Li Z, Heritier S, Arima H, Anderson CS; ChinaQUEST Investigators. Comparison of recovery patterns and prognostic indicators for ischemic and hemorrhagic stroke in China: the ChinaQUEST (QUality Evaluation of S — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Symptomatic intracranial hemorrhage(sICH)	Proportion of subjects with symptomatic intracranial hemorrhage (sICH) at 36 hours.	36 hours
Other	Death	Overall mortality rate at 90 days.	90 days
Other	Asymptomatic intracranial hemorrhage	Proportion of patients with asymptomatic intracranial hemorrhage at 90 days.	90 days
Other	Hemorrhage in other parts	The proportion of patients with other bleeding events was defined by GUSTO bleeding at 90 days.	90 days
Other	AE/SAE	Proportion of patients with adverse events / severe adverse events at 90 days.	90 days
Primary	National Institutes of Health Stroke Scale (NIHSS)	Proportion of subjects with NIHSS 1 or at least 4 on the NIHSS score decreased from the baseline at day14.	14 days
Secondary	Modified Rankin Scale (mRS)	Proportion of subjects of excellent outcome defined as mRS (0-1) at 90 days.; Ordinal distribution of mRS and change of proportion of subjects with mRS (0-2) at 90 days.	90 days
Secondary	National Institutes of Health Stroke Scale (NIHSS)	Neurological impairment defined as change of NIHSS score at 90 days.	90 days
Secondary	Barthel(BI)	Global function of daily living defined as BI = 95 at 90 days.	90 days
Secondary	EQ-5D	Quality of life measured by EQ-5D scale.	90 days