Trial Design and Oversight

In an international, multicenter, prospective, randomized, open-label trial with blinded outcome evaluation, two doses of intravenous alteplase were compared in patients with an acute ischemic stroke who were eligible for thrombolytic therapy; administration of the drug was commenced within 4.5 hours after the onset of the stroke. Patients with elevated systolic blood pressure (range, 150 to 220 mm Hg) could also be randomly assigned to early and intensive lowering of blood pressure (target systolic blood pressure <140 mm Hg within 1 hour) or conventional guideline-directed management of blood pressure (target systolic blood pressure <180 mm Hg) with the use of locally available intravenous agents.

Details of the design and statistical analysis plan of the trial have been published previously.13,14 An international steering committee, whose members designed the trial with an advisory committee, was responsible for the conduct and reporting of the trial. The George Institute for Global Health coordinated the trial, managed the database, and performed the analyses. The study drug used (alteplase) was that available for routine use at clinical centers; there was no commercial input into any aspect of the trial. The first author wrote the first and subsequent drafts of the manuscript. All the authors commented on drafts of the manuscript, approved the decision to submit the manuscript for publication, and vouch for the accuracy and completeness of the data and for the fidelity of this report to the trial protocol (available with the full text of this article at NEJM.org).

The trial protocol was approved by all appropriate regulatory authorities and ethics committees at the participating centers. All participants, or an approved surrogate for those who were too unwell to comprehend the information, provided written informed consent. Details of the monitoring procedures are provided in the Supplementary Appendix (available at NEJM.org).

Patients and Procedures

Patients were recruited at 111 clinical centers in 13 countries. Patients were eligible if they were 18 years of age or older, had an acute ischemic stroke, and met guideline-recommended criteria for treatment with intravenous alteplase. For details of the inclusion and exclusion criteria, see the Supplementary Appendix.

After confirmation of patient eligibility, randomization was performed centrally with the use of a minimization algorithm according to center, time from stroke onset (<3 vs. ≥3 hours), and severity of neurologic impairment (score of <10 vs. ≥10 on the National Institutes of Health Stroke Scale [NIHSS]; range, 0 to 42, with higher scores indicating greater severity of stroke). Participants were randomly assigned to receive either a standard dose of intravenous alteplase (0.9 mg per kilogram of estimated, or measured, body weight; 10% as a bolus and 90% as an infusion over a period of 60 minutes; maximum dose, 90 mg) or a low dose (0.6 mg per kilogram, 15% as a bolus and 85% as an infusion over a period of 60 minutes; maximum dose, 60 mg), to be commenced within 4.5 hours after symptom onset. Concomitant therapy followed national practice guidelines, including the use of endovascular thrombectomy devices, where approved.

Demographic and clinical data were obtained at the time of randomization. Follow-up data were obtained at 24 and 72 hours (including repeat NIHSS scores and measured body weight) and at 7 days (or hospital discharge, if sooner), 28 days, and 90 days, unless death occurred earlier. The 28-day and 90-day evaluations were conducted in person or by telephone, by trained and certified staff who remained unaware of the randomized treatment assignments. Brain imaging was performed at trial entry and at 24 hours, and additionally if clinically indicated, and was analyzed centrally for any hemorrhage by expert assessors who were unaware of the treatment assignments (see the Supplementary Appendix).

Outcomes

The prespecified primary outcome was the combined end point of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale,15 a global seven-level measure of functioning in which scores of 0 or 1 indicate a good outcome with no or minimal neurologic symptoms, scores of 2 to 5 indicate a poor outcome with increasing degree of disability, and 6 indicates death. The key secondary outcome, which was also designated as a safety outcome, was intracerebral hemorrhage, defined according to criteria from a number of other studies (see the Supplementary Appendix); the main definition of intracerebral hemorrhage that we used was the definition in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST)16: a large local or remote parenchymal pattern (>30% of the infarcted area affected by hemorrhage, with mass effect or extension outside the infarct) and neurologic deterioration from baseline (increase of ≥4 points in the NIHSS score) or death within 36 hours. This definition was finalized and described in the statistical analysis plan of our trial after publication of the original protocol.

Other secondary efficacy outcomes were the distribution of modified Rankin scale scores at 90 days,17 major disability (modified Rankin scale score >2) at 90 days, deaths at 7 days and 90 days, neurologic deterioration (increase of ≥4 points in the NIHSS score) during the 72 hours after randomization, death and neurologic deterioration (increase of ≥4 points in the NIHSS score) during the 72 hours after randomization, health-related quality of life on the EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D; summary health utility scores range from −0.109 to 1, with higher scores indicating better health)18 at 90 days (for details on scoring, see the Supplementary Appendix), length of initial hospital stay, recurrent acute myocardial infarction and recurrent ischemic stroke, admission to a long-term residential care facility at 90 days, and use of health services (for economic analyses that have not yet been conducted). Prespecified safety outcomes were all serious adverse events reported until trial completion. Tertiary outcomes included all-cause mortality, place of death, trends in modified Rankin scale scores during follow-up, length of stay in the intensive care unit (ICU), rate of thrombectomy, and individual items of the EQ-5D.

Statistical Analysis

We designed the trial to assess the effects of two treatment variables — alteplase dose and intensity of blood-pressure control — on clinical outcomes, accounting for their potential interaction.14 Differential patient recruitment resulted in the part of the trial dealing with alteplase dose being completed faster than the part dealing with intensity of blood-pressure control. For the primary analysis, we used an unadjusted logistic-regression model to test whether low-dose alteplase was noninferior to the standard dose. To satisfy the noninferiority hypothesis, the upper boundary of the 95% confidence interval for the odds ratio of the outcome with low-dose alteplase as compared with standard-dose alteplase had to fall below a margin of 1.14; this noninferiority margin was derived from a Cochrane meta-analyses of alteplase trials with effects on poor outcomes reported.19,20 We estimated that a sample size of 3300 patients would provide at least 90% power to evaluate noninferiority, assuming 5% dropout and potential negative interaction between intensive blood-pressure control and low-dose alteplase, and would also provide at least 80% power to detect superiority of low-dose alteplase in achieving a 40% lower risk of symptomatic intracerebral hemorrhage than that with standard-dose alteplase, with 5% dropout. Consistency of treatment effect across 10 prespecified subgroups was assessed through tests for interaction.

A secondary efficacy analysis was a comparison of ordinal scores on the modified Rankin scale to test for the noninferiority of the low dose to the standard dose with the use of ordinal logistic regression, after the assumption of proportionality of the odds was confirmed in a likelihood-ratio test.17 A new assumption-free approach21 was used to confirm the conclusion. We also performed secondary analyses of the primary outcome with adjustment for minimization and key prognostic covariates14, as well as secondary analyses in the per-protocol population according to criteria outlined in the Supplementary Appendix. Multiple imputation was to be used if more than 10% of observations were missing. An independent data and safety monitoring board monitored the trial progress and safety with the use of formal stopping boundaries. For ease of interpretation, all reported P values for noninferiority are multiplied by 2 so that an alpha of 0.05 can be used in analyses. The other P values (those for superiority) are two-sided. All P values were prespecified not to be adjusted. SAS software, version 9.3 (SAS Institute), was used for analyses.