Key Points
Question
Can the antioxidant drug Tongxinluo, which consists of 12 traditional Chinese herbs and medicines, improve short-term functional outcomes in patients with acute ischemic stroke?
Findings
In this randomized clinical trial that included 2007 participants with acute ischemic stroke randomized within 72 hours of symptom onset, oral administration of Tongxinluo for 90 days compared with placebo significantly improved the rate of favorable functional outcome (modified Rankin Scale score, 0 or 1) at 90 days.
Meaning
Among patients with acute mild-to-moderate ischemic stroke, Tongxinluo given within 72 hours of symptom onset improved clinical outcomes at 90 days; further research is needed to explore this outcome.
Abstract
Importance
Previous studies revealed limited effectiveness of neuroprotective agents in treating acute ischemic stroke (AIS). Tongxinluo, developed from traditional Chinese medicines, has been recognized as a novel neuroprotective agent with anti-inflammatory properties that stabilize vulnerable plaques in animal models and patients with myocardial infarction.
Objective
To assess the efficacy and safety of Tongxinluo in patients with acute ischemic stroke (AIS).
Design, Setting, and Participants
This multicenter, open-label, double-blind, randomized clinical trial included 2007 patients with AIS and a National Institutes of Health Stroke Scale score between 4 and 22 at admission. The trial was conducted at 50 hospitals in China from March 1, 2014, to October 31, 2016. Data were analyzed from November 14, 2016, to November 16, 2017.
Interventions
Eligible patients were randomized within 72 hours of symptom onset to the Tongxinluo group or the control group. Participants received 4 oral capsules of Tongxinluo or placebo, 3 times a day for 90 days. Other treatment was administrated according to guidelines.
Main Outcomes and Measure
The primary outcome was a favorable functional outcome at day 90 after randomization, defined as a modified Rankin Scale (mRS) score of 0 to 1 (on a scale of 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]). All statistical analyses were performed in a modified intention-to-treat population, defined as all patients who underwent randomization, were given any treatment, and underwent any posttreatment assessment.
Results
Among 2007 patients with AIS who were randomized, 1946 (96.5%) were included in the modified intention-to-treat analysis (973 in the Tongxinluo group and 973 in the control group, with mean [SD] age of 60.5 [9.2] years and 1342 [69.0%] male). Patients in the Tongxinluo group had a significantly higher proportion of favorable functional outcomes at day 90 compared with those in the control group (mRS score of 0-1, 640 [65.8%] vs 575 [59.1%]; odds ratio, 1.33 [95% CI, 1.11-1.60]; P = .002). The prespecified subgroup analyses indicated that, among all subgroups, additional Tongxinluo treatment had similar outcomes.
Conclusions and Relevance
Among patients with ischemic stroke within 72 hours after symptom onset, those additionally receiving Tongxinluo were more likely to have a favorable functional outcome, compared with a placebo group. Further research in patients with thrombolysis and endovascular treatment are needed to explore these outcomes.
Trial registration
ClinicalTrials.gov Identifier: NCT01919671
This randomized clinical trial investigates the effects of a traditional Chinese medicine formulation (Tongxinluo) compared with placebo on functional outcome in patients with acute ischemic stroke.
Introduction
Tongxinluo, an antioxidant drug, was reported to be associated with improved outcomes in patients with acute ischemic stroke (AIS) through protecting the blood-brain barrier, promoting axonal plasticity, stabilizing vulnerable plaques, and consequently inhibiting delayed neuronal death.1,2,3 Tongxinluo has been widely used in China to treat patients with acute unstable angina and was approved by China Food and Drug Administration in 1996.4,5 Tongxinluo consists of 12 traditional Chinese herbs and medicines: Boswellia carteri Birdw, Dalbergia odorifera T Chen, Panax ginseng C A Meyer Rhizome, Paeonia lactiflora Pallas, Ziziphus jujuba Mill var spinosa (Bunge) Hu H F Chou, Santalum album L, Borneolum syntheticum, Hirudo nipponica Whitman, Cryptotympana pustulata Fabricius, Buthus martensii Karsch, Steleophaga plancyi (Boleny), and Scolopendra subspinipes mutilans L Koch. Pharmacological studies have shown that Tongxinluo has vasodilatory, antiplatelet, anticoagulant, thrombolytic, and even lipid level–lowering effects and promising brain protection from ischemic injury.6
Stroke poses a major health and social economic burden worldwide,7 especially in China.8 As is known, reperfusion and neuroprotection are the 2 most effective strategies to the treatment of AIS. Reperfusion treatment has shown significant progress in AIS management in a limited time window.9 However, numerous phase 2 studies and dozens of phase 3 randomized clinical trials of neuroprotective agents have failed to show clinical efficacy.10
Previous studies11,12 have shown that Tongxinluo is safe in the treatment of AIS. In addition, Tongxinluo was associated with better neurologic function and a reduction of the recurrence rate of cerebrovascular events in patients with AIS.11,12 However, trials with a high level of scientific integrity are required to assess the efficacy and safety of a Tongxinluo capsule for AIS. This randomized clinical trial was designed to further investigate the effects of Tongxinluo vs placebo on 90-day functional outcome in patients with AIS.
Methods
Study Design
The Tongxinluo Capsule in Ischemic Stroke Patient (TISS) trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted at 50 centers in China from March 1, 2014, through October 31, 2016. The study protocol and statistical analysis plan are available in Supplement 1. The ethics committee from each study center approved this study, and all participants or their legally acceptable surrogates provided written informed consent.
The data safety monitoring board consisting of clinicians and biostatisticians supervised the clinical studies, especially the safety and completeness of data. The study was conducted in accordance with the principles of the Declaration of Helsinki13 and followed the Consolidated Standards of Reporting Trials (CONSORT) 2010 reporting guideline.
Study Population
Patients were screened to determine whether they met the following criteria: aged 35 to 75 years, ischemic stroke confirmed by magnetic resonance imaging or computed tomography, ability to receive the study agents within 72 hours of stroke onset, neurological deficits with a National Institutes of Health Stroke Scale (NIHSS) score between 4 and 22 at admission (scores range from 0-42, with higher scores indicating more severe stroke), first-ever stroke, or previous stroke without disability (modified Rankin Scale [mRS] score, 0-1; scores range from 0-6, with 6 indicating death). The exclusion criteria consisted of (1) hemorrhagic stroke according to head computed tomography or magnetic resonance imaging, including hemorrhagic stroke, epidural hematoma, intracranial hematoma, intraventricular hemorrhage, subarachnoid hemorrhage, and hemorrhage after cerebral infarction; (2) transient ischemic attack (TIA); (3) coma or unconsciousness, NIHSS category 1a score of greater than 1; (4) swallowing impairment or inability to take oral capsules; (5) stroke caused by brain tumor, brain trauma, or hemopathy; (6) hemorrhagic tendency; (7) endovascular treatment after the onset of stroke; and (8) severe cognitive impairment, late-phase Parkinson disease, or psychiatric disorders. The detailed exclusion criteria are provided in Supplement 1.
Randomization, Blinding, and Intervention
The randomization numbers were assigned using an automated centralized randomization system, with details summarized in Supplement 1. Randomization numbers were generated independently by a statistician from the Peking University Clinical Institute using SAS software, version 9.4 (SAS Institute Inc). The allocation of drugs was conducted independently by professional nurses. A comprehensive blinding protocol was implemented to safeguard treatment allocation concealment before randomization among participants, investigators, and other trial personnel. To maintain blinding integrity, placebo granules were meticulously matched with Tongxinluo in terms of color, odor, taste, shape, texture, specifications, appearance, packaging, labeling, and identification, making it virtually impossible for participants to distinguish them. Patients received Tongxinluo or placebo as 4 oral capsules, 3 times a day, for 90 days.
Outcomes
The primary efficacy outcome was the proportion of patients with an mRS score of 1 or less at 90 days after randomization. Subgroup analyses for the primary outcome were conducted, based on the Trial of Org 10172 in Acute Stroke Treatment classification, reperfusion treatment, stroke severity, time from AIS onset to randomization, age, sex, treatment, body mass index, hypertension, and diabetes.
The secondary efficacy outcomes measured the proportion of patients recovered to an NIHSS score of 0 to 1 or reduction by 4 points or more at 90 days, the proportion of patients with a Barthel Index (BI) score of 85 or more (scores range from 0-100, with higher scores indicating more independence in activities of daily living) at 90 days, distribution of scores on the mRS (ordinal shift analysis) at 90 days, incidence of ischemic cerebrovascular disease (ischemic stroke, TIA), and incidence of new combination clinical vascular events (ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction, vascular death). The safety outcomes were measured as the incidence of adverse and serious adverse events.
Statistical Analysis
Data were analyzed from November 14, 2016, to November 16, 2017. A sample size of 1968 patients would provide 80% power to detect a relative risk improvement of 7% in the Tongxinluo group compared with the placebo group, with a 2-sided type I error of .05, assuming an event rate of 40% in the placebo group and a 20% overall rate of withdrawal.
All statistical analyses were performed in the modified intention-to-treat (mITT) population, defined as all the patients who underwent randomization, were given any treatment, and underwent any posttreatment assessment. All the patients who received any study treatment were included in the safety outcomes analysis.
Categorical variables in the baseline characteristics were presented as counts with percentages. Continuous variables were presented as median (IQR). In the event of missing data for efficacy outcome variables, the last observation carried forward approach was used to impute missing data. Binary outcomes, including primary efficacy outcome (mRS score of 0-1 at 90 days), secondary efficacy outcomes (NIHSS score of 0-1 or improvement by ≥4 points; BI score ≥85) were compared between the 2 groups with the Cochran-Mantel-Haenszel method for controlling central effect. For the mRS score at 90 days, ordinal logistic regression analysis was conducted. In addition, the treatment effects (primary outcome) were analyzed among several prespecified subgroups by testing the treatment × subgroup interaction effect with the use of logistic regression models. All the tests were 2 sided, and P < .05 was considered statistically significant. All statistical analyses were performed using SAS software, version 9.4.
Results
Baseline Characteristics
Among the 2158 patients with AIS screened, 2007 were randomized, among whom 28 did not receive any treatment, and thus 1979 patients were included in the safety analysis. The outcome data were not available for 61 of the 2007 patients, and therefore 1946 patients (973 receiving Tongxinluo and 973 receiving placebo) were included in the mITT efficacy analysis. The mean (SD) age of the patients was 60.5 (9.2) years, 604 (31.0%) were female, and 1342 (69.0%) were male. The demographic and other baseline characteristics of patients were shown in Table 1 and eTables 1 and 2 in Supplement 2. There were 1677 participants (840 in the Tongxinluo group and 837 in the placebo group) without major violations of the study protocol and therefore included in the per protocol analysis (Figure 1).
Table 1. Baseline Characteristics of the Patients.
| Characteristic | Patient group, No. (%)a | |
|---|---|---|
| Tongxinluo (n = 973) | Placebo (n = 973) | |
| Age, median (IQR), y | 61.3 (54.4-67.5) | 60.9 (53.1-67.3) |
| Sex | ||
| Men | 677 (69.6) | 665 (68.3) |
| Women | 296 (30.4) | 308 (31.7) |
| BMI, median (IQR) | 24.2 (22.5-26.0) | 24.2 (22.5-26.1) |
| TOAST classification | ||
| Large artery atherosclerosis | 650 (66.8) | 645 (66.3) |
| Cardioembolism | 32 (3.3) | 21 (2.2) |
| Small-vessel occlusion | 250 (25.7) | 261 (26.8) |
| Other determined cause | 17 (1.7) | 13 (1.3) |
| Undetermined cause | 24 (2.5) | 33 (3.4) |
| Time from presentation to randomization, h | ||
| <12 | 41 (4.2) | 52 (5.3) |
| 12-48 | 440 (45.2) | 424 (43.6) |
| 49-72 | 492 (50.6) | 497 (51.1) |
| Medical history | ||
| Previous ischemic stroke | 180 (18.5) | 192 (19.7) |
| Hypertension | 592 (60.8) | 592 (60.8) |
| Diabetes | 252 (25.9) | 252 (25.9) |
| Angina | 0 | 2 (0.2) |
| Myocardial infarction | 3 (0.3) | 4 (0.4) |
| Atrial fibrillation | 18 (1.8) | 9 (0.9) |
| Hyperlipidemia | 28 (2.9) | 27 (2.8) |
| Smoking | 378 (38.8) | 395 (40.6) |
| Alcohol abuse | 270 (27.7) | 285 (29.3) |
| Therapeutic medication for stroke | ||
| Antiplatelets | 944 (97.0) | 942 (96.8) |
| Single | 482 (49.5) | 481 (49.4) |
| Dual | 462 (47.5) | 461 (47.4) |
| Statins | 771 (79.2) | 758 (77.9) |
| Anticoagulants | 79 (8.1) | 71 (7.3) |
| Batroxobinb | 114 (11.7) | 126 (12.9) |
| Neuroprotective agentb | 942 (96.8) | 946 (97.2) |
| Thrombolytics | 49 (5.0) | 52 (5.3) |
| Baseline NIHSS scorec | ||
| Median (IQR) | 5 (4-6) | 5 (4-7) |
| 4 | 322 (33.1) | 327 (33.6) |
| 5-8 | 569 (58.5) | 561 (57.7) |
| 9-12 | 72 (7.4) | 70 (7.2) |
| 13-16 | 5 (0.5) | 9 (0.9) |
| ≥17 | 5 (0.5) | 6 (0.6) |
| Prestrike mRS score, median (IQR)d | 2 (1-3) | 2 (1-3) |
| Baseline BI score, median (IQR)e | 70 (60-90) | 70 (60-90) |
| Systolic blood pressure, median (IQR), mm Hg | 148 (135-162) | 148 (132-160) |
| Diastolic blood pressure, median (IQR), mm Hg | 88 (80-96) | 88 (80-96) |
| Fasting glucose level, median (IQR), mg/dL | 90.1 (72.1-108.1) | 90.1 (72.1-126.1) |
| LDL-C level, median (IQR), mg/dL | 109.3 (89.2-1321.3) | 111.2 (89.2-132.8) |
Abbreviations: BI, Barthel index; BMI, body mass index (calculated as the weight in kilograms divided by the height in meters squared); LDL-C, low-density lipoprotein cholesterol; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; TOAST, Trial of Org 10172 in Acute Stroke Treatment.
SI conversion factors: To convert glucose to mmol/L, multiply by 0.0555; LDL-C to mmol/L, multiply by 0.0259.
Unless otherwise indicated, data are expressed as No. (%) of patients.
Detailed batroxobin and neuroprotective agents are listed in Supplement 1.
Scores range from 0 to 42, with higher scores indicating more severe stroke.
Scores range from 0 (no neurologic deficit, no symptoms, or completely recovered) to 6 (death).
Scores range from 0 (completely dependent) to 100 (completely independent) in activities of daily living.
Figure 1. Study Flowchart.
mITT indicates modified intention-to-treat; mRS, modified Rankin Scale (higher scores indicate worse function); NIHSS, National Institutes of Health Stroke Scale (higher scores indicate more severe stroke).
Efficacy Outcomes
The results of the primary efficacy outcome analysis are shown in Table 2 and Figure 2. A total of 640 patients (65.8%) in the Tongxinluo group and 575 (59.1%) in the placebo group had an mRS score of 1 or less on day 90 (odds ratio [OR] 1.33 [95% CI, 1.11-1.60]; P = .002). Per-protocol analysis showed similar results (eTable 3 in Supplement 2): 585 (69.6%) patients in the Tongxinluo group and 516 (61.6%) patients in the placebo group had an mRS score of 1 or less on day 90 (OR, 1.43 [95% CI, 1.17-1.75]; P < .001).
Table 2. Efficacy Outcomes According to Assigned Treatment.
| Outcome | Patient groupa | Risk difference (95% CI) | OR (95% CI) | |
|---|---|---|---|---|
| Tongxinluo (n = 973) | Placebo (n = 973) | |||
| Primary | ||||
| mRS 0-1 at 90 db | 640 (65.8) | 575 (59.1) | 6.68 (2.38 to 10.95) | 1.33 (1.11 to 1.60) |
| Secondary | ||||
| mRS 0-2 at 90 db | 835 (85.8) | 801 (82.3) | 3.49 (0.24 to 6.75) | 1.30 (1.02 to 1.66) |
| mRS, median (IQR)b | 1 (0-2) | 1 (1-2) | NA | 0.75 (0.64 to 0.88) |
| Ordinal distribution of mRS at 90 db | ||||
| 0 | 290 (29.8) | 233 (23.9) | NA | NA |
| 1 | 350 (36.0) | 342 (35.1) | NA | NA |
| 2 | 195 (20.0) | 226 (23.2) | NA | NA |
| 3 | 110 (11.3) | 142 (14.6) | NA | NA |
| 4 | 28 (2.9) | 29 (3.0) | NA | NA |
| 5 | 0 | 1 (0.1) | NA | NA |
| NIHSS score 0-1 or reduction of 4 points at 90 dc | 647 (75.8) | 588 (69.0) | 6.75 (2.50 to 10.96) | 1.40 (1.13 to 1.74) |
| BI score ≥85 or more at 90 dd | 727 (85.1) | 693 (81.3) | 3.79 (0.24 to 7.33) | 1.31 (1.02 to 1.70) |
| Ischemic cerebrovascular disease | 52 (5.3) | 56 (5.8) | −0.41 (−2.47 to 1.65) | 0.92 (0.63 to 1.36) |
| New combination vascular event | 58 (6.0) | 60 (6.2) | −0.21 (−2.35 to 1.94) | 0.96 (0.66 to 1.40) |
| Ischemic stroke | 43 (4.4) | 42 (4.3) | NA | NA |
| Hemorrhagic stroke | 4 (0.4) | 3 (0.3) | NA | NA |
| Transit ischemic attack | 10 (1.0) | 14 (1.4) | NA | NA |
| Myocardial infarct | 1 (0.1) | 0 | NA | NA |
| Vascular death | 2 (0.2) | 6 (0.6) | NA | NA |
Abbreviations: BI, Bathel Index; mRS, modified Rankin Scale; NA, not applicable; NIHSS, National Institute of Health stroke scale; OR, odds ratio.
Unless otherwise indicated, data are expressed as No. (%) of patients.
Scores range from 0 (no neurologic deficit, no symptoms, or completely recovered) to 6 (death).
Scores range from 0 to 42, with higher scores indicating more severe stroke.
Scores range from 0 (completely dependent) to 100 (completely independent) in activities of daily living.
Figure 2. Distribution of the Modified Rankin Scale (mRS) Scores on Day 90.
Scores range from 0 (no neurologic deficit, no symptoms, or completely recovered) to 6 (death). ITT indicates intention to treat.
The results of analyses for the secondary outcomes are shown in Table 2. Treatment with the Tongxinluo medication also resulted in a higher rate of mRS scores of 0 to 2 than placebo (OR, 1.30 [95% CI, 1.02-1.66]; P = .04). The Tongxinluo group also had the higher proportion of patients with an NIHSS score reaching 0 to 1 or a reduction of more than 4 points (OR, 1.40 [95% CI, 1.13-1.74]; P = .002) and patients with a BI score of 85 or greater (OR, 1.31 [95% CI, 1.02-1.70]; P = .04) (eTable 4 in Supplement 2). An ordinal comparison of the distribution of patients across the mRS categories showed that good functional outcome favored the Tongxinluo group (OR, 0.75 [95% CI, 0.64-0.88]; P = .001) (Figure 2) at 90 days. Tongxinluo treatment had no effect on new recurrent ischemic cerebrovascular disease (OR, 0.92 [95% CI, 0.63-1.36]; P = .69) or the new combination of clinical vascular events (OR, 0.96 [95% CI, 0.66-1.40]; P = .85).
The results of prespecified subgroup analyses are shown in Figure 3. No prespecified factor modified the treatment effect. In addition, patients younger than 60 years, with symptom onset within 48 hours, and with diabetes seemed more likely to benefit from the Tongxinluo treatment.
Figure 3. Prespecified Subgroup Analysis of the Primary Outcome.
The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 or 1 on the modified Rankin Scale (range, 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]) at 90 days. BMI indicates body mass index (calculated as the weight in kilograms divided by the height in meters squared); LAA, large artery atherosclerosis; OR, odds ratio; SAO, small-artery occlusion; and TOAST, Trial of Org 10172 in Acute Stroke Treatment.
Safety Outcome
The analysis of the safety outcome indicated that the 2 treatment groups (989 in the Tongxinluo group and 990 in the placebo group) had similar incidences of adverse events (382 [38.6%] vs 380 [38.4%]; P = .95) and serious adverse events (22 [2.2%] vs 19 [1.9%]; P = .64). Details are provided in eTable 6 in Supplement 2.
Discussion
This randomized clinical trial showed that patients with AIS receiving Tongxinluo had better 90-day favorable functional outcomes compared with the placebo group, patients younger than 60 years, with symptom onset within 48 hours, and with diabetes. In the last 10 years, no significant benefits for patients with stroke have been reported following a series of clinical trials targeting neuroprotection, including the SAINT (Stroke–Acute Ischemic NXY Treatment) I and II trials,14,15,16 the ESCAPE-NA1 (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischaemic Stroke) trial,17 the ALIAS (High-Dose Albumin Treatment for Acute Ischaemic Stroke) trials, 18,19 the URICO-ICTUS (Safety and Efficacy of Uric Acid in Patients With Acute Stroke) trials, 20,21,22 the FAST-MAG (Field Administration of Stroke Therapy–Magnesium) trial,23 and ACTION (Safety and Efficacy of Natalizumab in Patients With Acute Ischemic Stroke).24,25 Of note, all of those neuroprotection agents have a specific target or show a definite benefit on the pathway in preclinical studies. However, for brain ischemia, many pathways of damage in the ischemic cascades worsen simultaneously and might interact with each other, and hence, the most important question is whether interference with a single-pathway protection mechanism could lead to clinical benefits. A combination neuroprotection pathway targeting several pathways of ischemic injury might have advantages over a single-pathway strategy.
Tongxinluo has been shown to protect against inflammatory, stress, and apoptotic insults. The Tongxinluo capsule includes 12 chemical components that are thought to have vasodilatory, antiplatelet, anticoagulant, thrombolytic, and even lipid level–lowering properties and therefore might enhance poststroke protection effects.6 In a recent randomized clinical trial,26 Tongxinluo as an adjunctive therapy to guideline treatments for ST-segment elevation myocardial infarction demonstrated notable improvements in both 30-day and 1-year clinical outcomes. Our study further confirmed that patients treated with Tongxinluo had a significantly higher rate of the 90-day favorable functional outcome than patients treated with the placebo. Moreover, there was no difference in the rate of adverse events or serious adverse events between the Tongxinluo and placebo groups. Our study provides evidence that Tongxinluo capsules can improve patients’ neurologic functional deficits after AIS, with few adverse reactions.
The window for reperfusion treatment of patients with AIS is relatively narrow. Although encouraging results have been found in thrombectomy studies of highly selected patients treated within 24 hours,17,27,28 the efficacy of the neuroprotective agent used beyond the first few hours of AIS needs further investigation. As mentioned, most previous neuroprotective drug trials also require administration within 12 hours after onset.14,15,16,17,18,19,20,21,22,23,24,25 Several ongoing trials10,29 have enrolled patients using a longer time window of up to 48 hours after AIS onset. Therefore, limited experimental data are available to support the initiation of treatment with any neuroprotective agent beyond the first few hours after stroke onset.
Limitations
This study has several limitations. First, patients with severe stroke and those treated with endovascular procedures were not included, since those patients might not be able to swallow. Neuroprotective drugs should be evaluated in patients receiving endovascular thrombectomy in future studies. Second, the sample sizes in our subgroup analyses tended to be small, and, therefore, the results must be interpreted with caution. It is worth noting that although we found a significant difference in outcomes favoring the Tongxinluo group, the effect power in any prespecified subgroup was lacking, especially those with severe stroke and with reperfusion treatment. Third, this trial was conducted in China, and the findings may not be easily generalizable to other populations. The efficacy of Tongxinluo should be further investigated in other populations.
Conclusions
In this randomized clinical trial, patients with ischemic stroke who received Tongxinluo within 72 hours after symptom onset were more likely to have a favorable functional outcome at 90 days, particularly patients with mild to moderate stroke, compared with the placebo group. Further research in patients with thrombolysis and endovascular treatment are needed to explore these outcomes.
Trial Protocol and Statistical Analysis Plan
eTable 1. Comparison of Baseline Characteristics Between Those Patients With Protocol Violation and ITT Population
eTable 2. Distinction for Missing Completely at Random (MCAR)
eTable 3. Sensitivity Analysis on Primary Outcome (90 days mRS 0-1)
eTable 4. The Distribution of Baseline NIHSS and Change From Baseline in NIHSS Score and BI Score After 90 Days
eTable 5. Adherence by Different Treatment Groups
eTable 6. The Incidence of Serious Adverse Events by Different Treatment Groups
Nonauthor Collaborators. The TISS Trial Investigators
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol and Statistical Analysis Plan
eTable 1. Comparison of Baseline Characteristics Between Those Patients With Protocol Violation and ITT Population
eTable 2. Distinction for Missing Completely at Random (MCAR)
eTable 3. Sensitivity Analysis on Primary Outcome (90 days mRS 0-1)
eTable 4. The Distribution of Baseline NIHSS and Change From Baseline in NIHSS Score and BI Score After 90 Days
eTable 5. Adherence by Different Treatment Groups
eTable 6. The Incidence of Serious Adverse Events by Different Treatment Groups
Nonauthor Collaborators. The TISS Trial Investigators
Data Sharing Statement