Multimode computed tomography evaluation of the efficacy and safety of an extended thrombolysis time window (3–9 hours) for acute ischemic stroke: study protocol for a retrospective clinical trial based on medical records
Xue-Yuan Li1, Wei Sun1, Ying Yang1, Xin Zhang1, Dong-Mei Li2, Hong-Zhi Wang1, Xin-Ning Sui1, Hong Chang1, Xiu-Han Teng1, Teng Hu1, Jing-Bo Zhang1
1 The Third People's Hospital of Dalian, Dalian, Liaoning Province, China
2 Department of Medical Affairs, Techpool Bio-pharma Co., Ltd., Guangzhou, Guangdong Province, China
|Date of Web Publication||15-May-2018|
The Third People's Hospital of Dalian, Dalian, Liaoning Province
Source of Support: None, Conflict of Interest: None
Background and objectives: Intravenous thrombolysis with recombinant tissue plasminogen activator within 3 hours of acute ischemic stroke onset can reduce the risk of death and severe disability. There are differences in collateral circulation, the compensatory ability of cerebral blood vessels, and brain metabolism between each patient, leading to differences in the thrombolysis time window. Thrombolysis is considered effective in patients 3 hours after onset; however, it remains controversial whether this time window should be extended. Therefore, we will employ a retrospective case analysis study using multimode computed tomography (CT) to observe the extended time window (3–9 hours after stroke onset) and to summarize its efficacy and safety in the treatment of acute ischemic stroke.
Design: This is a retrospective, single-center, case-analysis clinical trial.
Methods: We will retrospectively collect data from 450 patients with acute ischemic stroke who have undergone thrombolytic therapy in the Third People's Hospital of Dalian, China, from June 2008 to December 2017. The time window will be set to 3–9 hours after stroke onset. We will evaluate the effect of this extended thrombolysis time window using multimode CT.
Outcome measures: The primary outcome measure is the National Institutes of Health Stroke Scale (NIHSS) score 7 days after treatment or at discharge, to evaluate the effect of thrombolysis. The secondary outcome measures are as follows: the occurrence of hemorrhagic events 24–36 hours and 7 days after treatment; NIHSS score at 2 and 24–36 hours, and at 3 and 12 months after treatment; modified Rankin scale score at 7 days after treatment or discharge, and at 3 and 12 months after treatment; vascular stenosis and infarct size 24–36 hours and 7 days after treatment; incidence of adverse reactions and deaths at 3 months after treatment; incidence of symptomatic intracranial hemorrhagic transformation during hospitalization; vital signs and laboratory measurements (blood indexes, blood glucose, blood lipids, liver and kidney functions, myocardial enzymes, blood electrolytes, and coagulation function); and electrocardiography results.
Discussion: Under the guidance of multimode CT, we will extend the thrombolysis time window to 9 hours after the onset of the disease, and summarize the efficacy and adverse reactions of an extended time window for intravenous thrombolysis after acute ischemic stroke. This trial will provide objective data for the optimization of clinical diagnoses and treatment pathways for patients.
Ethics and dissemination: This trial has been approved by the Medical Ethics Committee of The Third People's Hospital of Dalian, China on December 5, 2017. The study protocol will be conducted in accordance with the Declaration of Helsinki, formulated by the World Medical Association. This trial was designed in October 2017. Data collection has begun in January 2018 and will finish in October 2018. Outcome measures will be analyzed in December 2018. The results of the trial will be reported in a scientific conference or disseminated in a peer-reviewed journal.
Trial registration: This trial had been registered in the Chinese Clinical Trial Registry (registration number: ChiCTR1800014368). Protocol version (1.0).
Keywords: acute ischemic stroke; time window; intravenous thrombolysis; neurological deficit; multimode computed tomography
|How to cite this article:|
Li XY, Sun W, Yang Y, Zhang X, Li DM, Wang HZ, Sui XN, Chang H, Teng XH, Hu T, Zhang JB. Multimode computed tomography evaluation of the efficacy and safety of an extended thrombolysis time window (3–9 hours) for acute ischemic stroke: study protocol for a retrospective clinical trial based on medical records. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:8-17
|How to cite this URL:|
Li XY, Sun W, Yang Y, Zhang X, Li DM, Wang HZ, Sui XN, Chang H, Teng XH, Hu T, Zhang JB. Multimode computed tomography evaluation of the efficacy and safety of an extended thrombolysis time window (3–9 hours) for acute ischemic stroke: study protocol for a retrospective clinical trial based on medical records. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2018 May 22];3:8-17. Available from: http://www.actnjournal.com/text.asp?2018/3/2/8/232076
| Introduction|| |
Acute ischemic stroke is the most common type of stroke, accounting for 60–80% of all strokes (Group of Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke in the Cerebrovascular Disease Section of the Neurology Branch of the Chinese Medical Association, 2010). Following a stroke, patients not only suffer from impaired physiological functions, but may also have mental disorders and social dysfunction that seriously affect their quality of life (Liang et al., 2017; Joo et al., 2017). Therefore, research into stroke prevention and treatment is of great significance. At present, there are clear guidelines for the effectiveness of thrombolysis within 3 hours after onset of an acute ischemic stroke (Jauch et al., 2013).
There are many factors that affect the effectiveness of thrombolysis for acute ischemic stroke, including the thrombolysis time window, the efficacy of the thrombolytic drugs, the thrombolysis pathway, and the patient's own condition (Rha and Saver, 2007). Among them, the thrombolysis time window is the most critical factor (Hacke et al., 2004; Kellert et al., 2017; Soeteman et al., 2017). Performing thrombolysis within an effective time window can not only save the remaining ischemic penumbra in time, but also markedly reduce many thrombolysis-related complications, including cerebral edema, hemorrhagic transformation, and reperfusion injury, and thereby improve a patient's prognosis and reduce mortality in thrombolysis patients (Kamal et al., 2017; Mehta et al., 2017; Vuong et al., 2017). Research into ways of extending the thrombolysis time window is very important, as this will allow thrombolysis to be used more than 3 hours following an acute ischemic stroke. In recent years, many studies have examined the prognosis of acute ischemic stroke patients treated with thrombolysis. In [Table 1], we summarize three representative clinical studies (Norby et al., 2013; Berge et al., 2015; Thomalla et al., 2017).
|Table 1: Representative clinical studies on thrombolysis for acute ischemic stroke published from 2013 to 2017|
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Because of its speed of imaging and sensitivity to hemorrhage, computed tomography (CT) is suitable for emergency patients and is the preferred imaging method for cerebrovascular disease. CT examination includes a plain scan, a CT perfusion (CTP), and a CT angiography (CTA). The use of multi-slice spiral CT gives a “one-stop” examination for acute stroke patients in the clinic. First, a plain CT scan is conducted to eliminate hemorrhagic disease. Second, CTP is used, and finally, CTA is performed during the post-processing of CTP images. All scans can be finished in 20 minutes. Thus, comprehensive information from the plain CT scan, and about cerebral blood flow perfusion and blood supply, is obtained. This information provides a timely, detailed, and accurate imaging basis for clinical diagnosis and treatment. It also shortens the time of examination and diagnosis, and it is of great significance for emergency thrombolysis treatment (Hitchen et al., 2016).
Novelty of this study
The trial is a retrospective, single-center clinical study based on medical records. With multimode CT, patients were selected to extend the thrombolysis time window. Clinical outcomes of thrombolysis patients were assessed 3 to 9 hours after the onset of acute ischemic stroke (DAIS-2 Neurology December 18, 2008). Assessment was performed in the baseline, treatment, and follow-up periods to determine the efficacy and safety of this treatment in each period.
The aim of this trial is to analyze whether extending the thrombolysis time window for treating acute ischemic stroke, using multimode CT images for guidance, can improve patient outcomes. This trial also aims to provide objective support for the optimization of the clinical diagnosis and treatment pathway, so that more patients receive thrombolysis.
| Methods/Design|| |
This is a retrospective, single-center, case-analysis clinical trial. The flow chart of the trial is shown in [Figure 1].
The Third People's Hospital of Dalian, Dalian, Liaoning Province, China.
The data of patients who have undergone thrombolysis for acute ischemic stroke will be collected from the Medical Records Room of the Third People's Hospital of Dalian.
- Baseline: Demographic data, history, onset and admission, vital signs, and imaging results. The following clinical data will also be collected as much as possible: electrocardiography results and laboratory measurements (blood indexes, blood glucose, blood lipids, liver and kidney functions, myocardial enzymes, blood electrolytes, and coagulation function); Glasgow Coma Scale score, Essen Stroke Risk score, National Institutes of Health Stroke Scale (NIHSS) score, and modified Rankin Scale score.
- Hospitalization: Laboratory measurements, thrombolysis (time and dosage, bleeding), CT examination results 24–36 hours and 7 days after treatment, and NIHSS scores 2 hours, 24 hours, and 7 days after treatment.
- Discharge: We will record the patient's in-hospital treatment program, vital signs, the results of electrocardiogram and aforementioned laboratory tests, and assess Glasgow Coma Scale score, NIHSS score, and modified Rankin Scale score.
- Follow-up period: If we can get in contact with the patient, we will assess the modified Rankin Scale and NIHSS scores, imaging findings, and medication, either by telephone or in an outpatient clinic at 3 and 12 months after treatment.
In addition, the investigator will collect information about all adverse events and medications that occurred during admission.
The above data will be collected in non-intervention situations and as completely as possible, but if there are gaps in the data, it will not be considered a deviation. CT examination results include the results of plain CT scans, CTP, and CTA. After the baseline imaging examination, images will be qualitatively evaluated by blinded imaging investigators (with no knowledge of the NIHSS score or medications).
Patients who meet all of the following criteria will be considered for study inclusion:
- Ischemic stroke and an assessable neurological deficit (such as speech, motor function, cognitive impairment, gaze impairment, visual field defect, and/or visual neglect). Ischemic stroke is defined as a sudden acute focal neurological deficit; the reason is presumed to be cerebral ischemia, and cerebral hemorrhage is excluded by CT (Jauch et al., 2013).
- Aged 18–85 years.
- The time window for new stroke symptoms or signs from onset to treatment is 3–9 hours.
- No obvious sequelae left on the first or previous stroke.
- Data of patients who conform to thrombolysis and meet the main evaluation criteria can be collected.
- Original CTA images that show an abnormal low density area involving the cerebral hemisphere with a diameter of > 2 cm, and the area of abnormal low density is less than one third of the middle cerebral artery.
Patients who meet one or more of the following conditions will be excluded from the study:
- Severe stroke confirmed by coma or clinical assessment (such as NIHSS score > 25) and/or other imaging.
- Stroke occurred within 3 months before admission.
- Heparin was applied within 48 hours before stroke onset, and the time of activating partial thromboplastin exceeded the upper limit of normal laboratory values.
- Creatinine value exceeded the normal range (> 133 μM).
- Platelet count < 100,000/mm3.
- Hypertension remained uncontrolled after active antihypertensive therapy. Uncontrolled hypertension refers to systolic blood pressure > 185 mmHg or diastolic blood pressure > 110 mmHg (1 mmHg = 0.133 kPa), measured three times at intervals of at least 10 minutes.
- Blood glucose < 2.7 mM or > 22.2 mM.
- Obvious hemorrhagic diseases at the time of admission or in the previous 6 months.
- Oral anticoagulant drug (such as warfarin) use, international normalized ratio >1.5.
- Known history of intracranial hemorrhage or a suspected intracranial hemorrhage (including subarachnoid hemorrhage).
- Pregnancy or lactation.
- History of severe central nervous system damage (such as a tumor, aneurysm, or intracranial or spinal surgery).
- Hemorrhagic retinopathy, such as diabetes (visual disorders may suggest retinal hemorrhage) or other hemorrhagic eye disorders.
- Bacterial endocarditis and pericarditis.
- Prolonged or traumatic cardiopulmonary resuscitation (> 2 minutes), delivery within 10 days before admission, or a recent non-pressure vascular (subclavian or jugular veins) puncture.
- Acute pancreatitis.
- Ulcerative gastrointestinal disease (within 3 months).
- Aneurysm, arteriovenous malformation.
- Tumor that increases the risk of bleeding.
- Severe liver disease, including liver failure, cirrhosis, portal hypertension (esophageal varices), and active hepatitis.
- Major surgery or severe trauma, history of craniocerebral trauma in the 10 days before admission.
- Allergy to alteplase drugs.
- Imaging exclusion criteria: a. parenchymal hemorrhage, subarachnoid hemorrhage, or intracranial tumor; b. contraindications for imaging examination; c. any degree of high-density hemorrhagic shadow in any areas of brain parenchyma on the CT; d. remarkable signs of occupancy due to midline displacement induced by large-area cerebral infarction; e. light, unclear, low-density shadows at brain parenchyma beyond one third of the area of the middle cerebral artery or suspected infarcted lesions.
Randomization and blinding
As a retrospective case analysis, this study will not select random groups. It is only an observational trial. After the baseline imaging examination, the images will be qualitatively evaluated by blinded imaging investigators (without knowing NIHSS scores or medication).
- CT examination requirements: A multi-row spiral CT (40 rows or more; Siemens, Germany) will be used.Whole-brain plain CT scan: positioning: the supraorbitomeatal line is used as a reference plane scan to avoid direct irradiation of the lens; scanning range: from the skull base to the top of the head, including the whole brain; slice thickness: skull base surface, 3–5 mm, cerebral hemisphere, 8–10 mm.
CTP: positioning: in combination with plain CT scan and clinical information, two slices can be selected as the scanning plane in the lesion area. If it is a suspected supratentorial lesion, the basal ganglia and lateral ventricle body plane can be chosen to scan; scanning parameters: delay time 4 seconds, scanner time 40 seconds, spiral velocity 1 second, image reconstruction interval 1 frame/s; CTP reexamination is to guarantee the slice consistency; images will be analyzed using a unified image post-processing software.
CTA: scan range: whole brain; total dose of high-pressure syringe contrast agent is 50–90 mL, injected at a rate of 4 mL per second; CTA image post-processing: maximum intensity projection reconstruction and/or volume reconstruction. In the emergency state, at least one maximum intensity projection CTA parameter image is provided, and the Willis ring is required to be displayed. After the scan, the original data of the CTA is reconstructed, and the reconstruction thickness is the same as that of the CTP.
CT and multimode CT scans require consistency in the parameters of enrolled patients. The same patients must be consistent in baseline examination and reexamination.
- Specific treatment of acute ischemic stroke: an intervention on a specific aspect of the pathophysiological mechanisms of ischemic injury. Thrombolysis treatment collects the time from onset to thrombolysis and the use of a thrombolytic agent, recombinant tissue plasminogen activator. Use of other commonly used drugs are collected according to the specific conditions of use (examples are as follows): Antiplatelet drugs: aspirin, clopidogrel. Anticoagulant drugs: unfractionated heparin, low molecular weight heparin, heparinoids, oral anticoagulants, and thrombin inhibitors. Drugs for expansion: hydroxyethyl starch and low molecular dextran. Neuroprotective agents: edaravone, citicoline, and gangliosides. Drugs for improving cerebral blood flow infusion: butylphthalide and human urinary kallikrein. Chinese medicine: Shuxuetong and Danhong injections.
- Imaging assessment: All baseline/reexamined CT images (including plain CT scan, CTP, and CTA) will be evaluated by the investigator for technical adequacy. If the technical quality of the image is sufficient to interpret the analysis and the anatomical region covers the required range (field of view) sufficiently, then the patient's image can be used for diagnosis and to guide treatment. Baseline and reexamined images will be assessed by two blinded imaging experts with no knowledge of patients’ NIHSS scores. The technical quality of the image will be divided into three levels: good = distinct image, without “moving tail shadow”; medium = the image is less clear, with “moving tail shadow”, but it can still be used for diagnosis; poor = “moving tail shadow” of images is very obvious, and the lesion density/signal or site cannot be clearly displayed and cannot be used for diagnosis. Images can only be used for diagnosis and to guide treatment if image quality is evaluated as “good” or “medium”.CT assessment: 1) Exclusion of hemorrhage or space occupying. 2) Large-area CT scans of hyperacute cerebral infarction do not have distinct low-density areas. Careful observation often reveals shallow or occluded lateral sulcus. 3) Early signs of large-area cerebral infarction; the disappearance of gray and white matter demarcation; the shallow cerebral sulcus; low-density lesions > one third of the middle cerebral artery blood supply range; or obvious mass effect (ventricle compression and midline displacement). 4) The boundary between the putamen and the insular lobe on the affected side with insular ribbon sign is fuzzy, showing a positive change. The insular ribbon sign is a characteristic manifestation of cortical infarction in the middle cerebral artery distribution area, including the blurred boundary of the insular cortex and subcortical white matter, and slightly decreased density of the insular cortex, which is similar to that of the white matter [Figure 2]. 5) Hyperdense middle cerebral artery sign: The density of the middle cerebral artery on the affected side is increased, which is caused by vascular thrombosis or thrombosis [Figure 3]. The CT numbers are 77–89 Hu (normal: 42–53 Hu); and 114–321 Hu in calcific plaques of atherosclerosis.
|Figure 2: Plain CT scan images of a 68-year-old male patient with insular ribbon sign and hyperacute cerebral infarction of left frontotemporal cortex.|
Note: (A) Insular ribbon sign; (B) shallow left lateral sulcus; (C, D) a low density change in the infarct area of two slices, 3 days after treatment.CT: Computed tomography.
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|Figure 3: Hyperdense right middle cerebral artery sign in a 58-year-old female patient within 4 hours of cerebral infarction onset.|
Note: Bar high-density shadow.
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CTP assessment: 1) Observation of responsible focus perfusion: CTP indexes contain cerebral blood flow, cerebral blood volume, mean transit time, and time-to-peak [Figure 4]. 2)Assessment of ischemic penumbra: whether the CTP/CTA mismatch is ≥ 20% (the indicator used is mean transit time).
|Figure 4: Middle cerebral artery distribution area in the right frontal, temporal, and parietal lobes of a 65-year-old male patient within 6.5 hours of cerebral infarction onset.|
Note: (A) Decreased cerebral blood flow (CBF); (B) increased cerebral blood volume (CBV); (C) prolonged mean transit time (MTT); (D) prolonged time-to-peak (TTP).
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CTA assessment: 1) In the hyperacute infarct region on CTA source images, the window width and window position will be adjusted to observe the low density changes [Figure 5]. 2)CTA reveals the modified thrombolysis in cerebral infarction classification in great vessels: grade 0, vascular occlusion without forward blood flow through the occluded segment [Figure 6]A; grade 1, severe stenosis with forward blood flow, but there is no vascular branch at the distal end [Figure 6]B; grade 2, non-severe stenosis with forward blood flow and vascular branching at the distal end [Figure 6]C; grade 3, no stenosis or non-severe stenosis, with smooth forward blood flow and normal vascular branching at the distal end [Figure 6]D.
|Figure 5: Computed tomography angiography source images of brain tissue with hyperacute cerebral infarction.|
Note: (A) Left frontotemporal lobe shows flaky, low-density shadow and the border is still clear; (B) left frontoparietal lobe presents large-scale low-density changes.
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|Figure 6: Computed tomography angiography images of modified thrombolysis in cerebral infarction classification in great vessels.|
Note: (A-C) Grades 0, 1, and 3 of the right middle cerebral artery, respectively; (D) normal image of cerebral vessels (grade 3).
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- Follow-up requirements: Because the trial is a retrospective study, it is not possible to perform follow-up visits on previously treated patients and it is only possible to retrospectively review prior outpatient treatment.
- Observation time point setting: Baseline period: visit 1 (on admission, day 0); treatment period: visit 2 (hospitalization, no thrombolysis), 2 hours ± 15 minutes, 24–36 hours after thrombolysis started; visit 3 (7 days after thrombolysis or discharge); follow-up period: visit 4 (3 months after thrombolysis, checking outpatient and inpatient medical records); visit 5 (12 months after thrombolysis, checking outpatient and inpatient medical records).
Primary outcome measure
- NIHSS score 7 days after treatment or at discharge to assess thrombolytic effect: The NIHSS score is helpful for prognosis 7–10 days after acute stroke onset (Norby et al., 2013). The NIHSS score includes 11 items; the higher the score, the more severe the stroke condition (Brott et al., 1989).
Secondary outcome measures
- Occurrence of hemorrhagic events 24–36 hours and 7 days after treatment: There are four kinds of hemorrhage transformation after revascularization following a cerebral infarction: 1) Hemorrhagic infarction type 1, i.e., a small spot-like hemorrhage at the edge of the infarct. 2) Hemorrhagic infarction type 2, i.e., an inconclusive spot-like hemorrhage in the infarct zone, no significant mass effect. 3) Parenchymal hematoma type 1, i.e., hematoma volume ≤ 30% infarct size, with slight mass effect. 4) Parenchymal hematoma type 2, i.e., hematoma volume > 30% infarct size, with obvious mass effect or hemorrhage outside infarct foci (Hacke et al., 1998).
- NIHSS score during hospitalization (without thrombolysis), 2 hours, 24–36 hours, 3 months, and 12 months after treatment: The same scoring criteria as mentioned previously.
- Modified Rankin scale (mRS) score at 7 days or discharge, 3 months, and 12 months after treatment: The scale runs from 0–6, ranging from perfect health without symptoms to death. Grade 0, no symptoms; grade 1, no significant disability, able to carry out all usual activities despite some symptoms; grade 2, slight disability, able to look after own affairs without assistance, but unable to carry out all previous activities; grade 3, moderate disability, requires some help, but able to walk unassisted; grade 4, moderately severe disability, unable to attend to own bodily needs without assistance, unable to walk unassisted; grade 5, severe disability, requires constant nursing care and attention, bedridden, incontinent; grade 6, dead.
- Vascular stenosis and infarct size 24–36 hours and 7 days after treatment: Vascular stenosis and infarct size will be assessed using previous methods (van Swieten et al., 1988).
- Incidence of adverse reactions and deaths 3 months after treatment: The number of patients who experienced adverse reactions or death will be counted.
- Incidence of symptomatic intracranial hemorrhagic transformation during hospitalization: In accordance with a previous study (Hacke et al., 1998), incidence of symptomatic intracranial hemorrhagic transformation (European Cooperative Acute Stroke Study II) is equal to the number of patients with symptomatic intracranial hemorrhagic transformation/total number of patients × 100%.
- Vital signs, laboratory measurements, and electrocardiography results during hospitalization: Vital signs include body temperature, pulse, respiration, and blood pressure. In visit 1, changes in body temperature 24 hours after the onset of illness were collected. Laboratory measurements include blood indexes, blood glucose, blood lipids, liver and kidney functions, myocardial enzymes, blood electrolytes, and coagulation function. Electrocardiograms will be used to examine arrhythmia.
Adverse events/serious adverse events
In accordance with Good Clinical Practice (Bureau No. 3), Drug Adverse Reaction Reporting and Monitoring Management Measures (Ministry of Health of China No. 81), and Drug Registration Regulations (Bureau No. 28), investigators will carry out their relevant duties, and handle, record, and report adverse events/serious adverse events.
Definition and classification of adverse events
An adverse event refers to any adverse medical event that occurs after a patient or clinical study subject takes a drug. This event does not necessarily have a causal relationship with this treatment. Thus, an adverse event may be any unfavorable and unanticipated sign (including abnormal laboratory findings), symptoms, or disease that is temporally related to the use of a (study) drug, regardless of whether it is related to the drug.
Serious adverse events refer to any adverse medical events that appear to meet one or more of the following criteria at any dose:
- Fatality (causing death; note: death is a consequence, not an event)
- Life-threatening (Note: “life-threatening” refers to the immediate risk of death of the patient at the time of the incident, and does not necessarily imply death if the incident is severe)
- Events that cause significant or permanent impairment of the human body or organ function
- Teratogenic effects, birth defects
- Events that lead to hospitalization or extend a hospital stay
- Important medical events or interventions (if not treated, the above listed conditions may occur.)
Criteria for judging severity
Severity will be assessed according to the following grading description: Mild: perceivable, but tolerable, symptoms, causing mild discomfort but not disturbing daily activities. Moderate: discomfort affects daily life. Severe: very painful, causing significant functional damage or loss of self-care ability; cannot carry out normal daily activities. The investigator will not use the direct judgment of the subject, but will use clinical judgment to assess the severity of the event (such as abnormal laboratory and auxiliary examination results).
Reporting of adverse events
Requirements for reporting adverse events: Time limit: 24 hours. In clinical studies, regardless of the type of treatment, for any adverse event that occurs, the subject will immediately be given appropriate treatment. The investigator or authorized personnel will report adverse events to the drug supervision and administration departments of the provinces, autonomous regions, and municipalities directly under the Central Government within the time limit required by laws and regulations according to the Drug Adverse Reaction Reporting and Monitoring Management Measures (Ministry of Health of China No. 81).
Requirements for reporting serious adverse events: Time limit: 24 hours. In clinical studies, regardless of the type of treatment, for any adverse event that occurs, the subject will immediately be given appropriate treatment. In accordance with Good Clinical Practice (Bureau No. 3), Drug Adverse Reaction Reporting and Monitoring Management Measures (Ministry of Health of China No. 81) and Drug Registration Regulations (Bureau No. 28), the investigator or authorized personnel will report adverse events to the drug supervision and administration departments of the provinces, autonomous regions, and municipalities directly under the Central Government, other centers, and ethics committees within the time limit required by laws and regulations. For all serious adverse events, regardless of whether the subject has stopped or completed the treatment, the investigator will continue to monitor and report the event until the subject recovers, stabilizes or returns to baseline. Any follow-up information on serious adverse events will also be reported within 24 hours in accordance with the above process.
Outcome measurement assessments
The schedule of outcome measurement assessments is shown in [Table 2].
The trial is a retrospective study, and the cases are determined according to actual collection conditions based on the inclusion criteria. According to our hospital's annual average number of acute ischemic stroke patients receiving thrombolysis (90–100 cases), data from approximately 1000 patients will be collected from June 2008 to December 2017. An estimated 500 cases will be excluded according to the exclusion criteria. If we assume a loss rate of 10%, we will include approximately 450 cases in total.
All data will be analyzed using descriptive statistics. Measurement data will be expressed as the mean, median, standard deviation, the lower quartile (q1), upper quartile (q3), minimum and maximum. The 95% confidence interval of the mean will be calculated. Enumeration data will be expressed as the frequency and relative number. The 95% confidence interval of the rate will be calculated.
According to whether the score difference meets the normality before and after treatment, intragroup comparisons of measurement data will be analyzed using paired t-test or Wilcoxon signed-rank test. Enumeration data will be analyzed using chi-square test or Fisher's exact test. Ranked data will be analyzed using Wilcoxon rank sum test. The significance level will be α = 0.05.
Data sets: According to the intention-to-treat principle, this will be the data set of patients who receive at least one treatment regimen and have at least one post-baseline efficacy assessment.
Efficacy analysis: Efficacy indicators will be analyzed in full analysis set.
Changes in NIHSS score at discharge compared with baseline data. An analysis of variance will be performed if the difference between the scores before and after treatment satisfies normality and variance homogeneity. If this analysis reveals a statistically significant difference, the Bonferroni test will be used for pairwise comparison. Otherwise, the Kruskal-Wallis test will be carried out. If this test indicates statistical significance, the Wilcoxon rank-sum test will be used, and the Bonferroni method will be used to calibrate the P-values for pairwise comparison.
The proportion of patients with good prognosis (mRS score = 0–2), poor prognosis (mRS score = 3–5) and who die (mRS score = 6) at 90 days after treatment will be analyzed using descriptive statistics. Their numbers and proportions will be calculated. Intergroup differences will be compared using the chi-square test or Fisher's exact test. If the difference between groups is statistically significant, the Bonferroni test will be used to adjust the α-value for further pairwise comparison.
(5) Safety analysis: The safety will mainly be analyzed using descriptive statistics. Incidence of symptomatic intracranial hemorrhagic transformation during hospitalization will be compared using chi-square test or Fisher's exact test. Vital signs and laboratory measurements will be statistically described and compared with the baseline using paired t-test or signed rank test. Changes in laboratory and electrocardiogram results before and after treatment will be assessed by cross tabulation.
Data collection and management
Subject identification and subject screening records: The investigator will complete the subject registration form in a consistent and systematic manner so that the subject can be easily identified during and after the study. The subject's identity registration form is a confidential document, and investigators will keep it at the research center. To ensure confidentiality, this registration form will not be duplicated. All research-related reports and letters will use the subject's initials and numerical identifiers to describe the subject.
Data management requirements: According to the requirements of the study, we will design the case report form to optimize data collection. The timeline will be used to systematically collect and arrange the clinical data. As the study progresses, we may use an electronic data capture system for data collection. If there is any change, we will apply for ethics review.
Data quality assurance: The steps required to ensure the accuracy and reliability of the data include: Before the start of the study, we will train the relevant personnel involved in the study. We will carefully fill in the relevant information to ensure that the data are reliable. Moreover, to ensure the accuracy of the data, investigators will be required to periodically check the data by bidirectional verification until the end of the study.
Study completion: After the last visit of the last subject is completed, the full data set will be collected, and the investigator will inform the hospital ethics committee and the relevant person in charge that this study is finished.
Study termination: The trial sponsor reserves the right to terminate the study at any time. The reasons for terminating research/terminating research in a center may include, but will not be limited to: the number of enrolled patients does not reach the pre-determined requirements; trials that cannot be performed due to various external forces; recruitment of insufficient subjects.
Data monitoring committee composition
The data monitoring committee contains members who can properly perform their duties independently and play a guiding role for the data monitoring to ensure the integrity of the research and protect the safety of the participants.
Surgeons participating in imaging assessment have a wealth of neuroimaging assessment experience.
During the trial, the auditor will check the integrity and authenticity of all data records. All adverse events will be confirmed to be recorded and serious adverse events will be reported and recorded within the specified time.
There will be no laboratory or imaging test fees at reexamination.
Ethics and dissemination
This trial has been approved by the Medical Ethics Committee of The Third People's Hospital of Dalian of China on 5 December 2017. The study protocol will be conducted in accordance with the Declaration of Helsinki, formulated by the World Medical Association. The writing and editing of the article will be performed in accordance with the Standard Protocol Item: Recommendations for Interventional Trail (SPIRIT) (Additional file 1 [Additional file 1]).
The trial is a retrospective case collection study. During retrospective collection, because the patients have been discharged, it will not be possible to obtain informed consent. We guarantee not to collect content involving personal privacy, including personal identity. Personal contact information and the real name will not be leaked. If we are able to contact the patient during the telephone follow-up, we will request patient consent. The patient data will not be collected if the patient refuses consent. The collection and use of these data will fully ensure its confidentiality and protect the subject's privacy.
This is a case collection study initiated by the hospital department itself. The subject information collected will be mainly used for statistical analyses and eventual publication as a clinical research study. If appropriate, we might also combine our data with those of other hospitals for analysis and publication. In this case, we will indicate the source of the data. Moreover, participating investigators will be acknowledged as authors when the work is published. The data will be published in the form of articles 6 months after study completion. The results of the trial will be reported in a scientific conference or disseminated in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.
| Trial Status|| |
This retrospective clinical study based on medical records began in January 2018. Data collection and analysis are ongoing at the time of submission.
| Discussion|| |
Contributions and problems of previous studies in this field
To date, only ultra-early thrombolysis and antiplatelet therapy have been supported by evidence-based medicine in the treatment of ischemic stroke. Intravenous thrombolysis with recombinant tissue plasminogen activator within 3 hours of onset remarkably reduces the risk of death and severe disability. The European Cooperative Acute Stroke Study III suggests that it is also safe and feasible for patients within 3.0–4.5 hours of stroke to receive intravenous recombinant tissue plasminogen activator, which can also improve the prognosis of patients. The largest clinical trial of urokinase thrombolysis was conducted in China. A total of 465 acute ischemic stroke patients were enrolled from 51 centers. The results demonstrated that urokinase thrombolysis was safe and effective within 6 hours of stroke onset (Cooperaring Group for National 95's Project, 2002). Therefore, thrombolysis is currently classified as Type I evidence in the national guidelines worldwide. However, the actual proportion of patients undergoing thrombolysis is very low.
Characteristics of this study protocol
The efficacy and safety of thrombolytic therapy 3–9 hours after an acute ischemic stroke will be assessed using multimode CT. Observed indicators are comprehensive and the results can reflect the efficacy and prognosis of this therapy.
Limitations of this study
This is a retrospective study. The collection of case data is prone to selection bias. When accessing previous information, it is difficult to avoid recall bias. We will not set a control group, and this is only a descriptive analysis. The patients included are acute ischemic stroke patients, 3 to 9 hours after onset. They can be divided into 3, 4, 5, 6, 7, 8, and 9 hours for a total of seven time points. However, this trial will not conduct a stratified analysis of time. These four limitations will have an impact on the accuracy of the results and will be further refined in future research.
Significance of this study
We will understand neurological recovery, adverse reactions, and mortality in patients after thrombolysis within 3–9 hours of onset of an acute ischemic stroke. This will provide an objective reference for expanding the thrombolysis time window for acute ischemic stroke.
Additional file 1: SPIRIT checklist.
Study design: JBZ. Subject recruitment: XYL, WS and YY. Data collection and analysis: XYL, WS, YY, XZ, XNS, HC, XHT and HZW. Literature search and translation: DML. All authors approve the final version of the paper.
Conflicts of interest
The authors declare that the research is conducted in the absence of any commercial or financial relationships that can be construed as a potential conflict of interest.
The study receives no specific funding agency in the public, commercial, or not-for- profit sectors.
Institutional review board statement
This trial has been approved by the Medical Ethics Committee of The Third People's Hospital of Dalian of China on December 5, 2017. The study follows the Declaration of Helsinkis.
This study follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.
The statistical methods of this study were reviewed by the biostatistician of the Third People's Hospital of Dalian, China.
Copyright transfer agreement
The Copyright License Agreement has been signed by all authors before publication.
Data sharing statement
Individual participant data after deidentification (text, tables, figures, and appendices) will be in particular shared. Study protocol form will be available. The study protocol and clinical study report will be made public within 6 months after completion of the trial. The data will be available immediately following publication without end date. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.
Checked twice by iThenticate.
Externally peer reviewed.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]