Giving very late thrombolysis to patients with large-vessel occlusion small core strokes did not show a significant benefit in the TIMELESS trial.
However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.
The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.
"This is first trial to try giving a thrombolytic so late — up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings," lead author, Gregory Albers, MD, director of the Stanford Stroke Center and professor of neurology at Stanford University, California, told theheart.org | Medscape Cardiology.
"The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups," Albers said.
"And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study," he added.
The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.
Albers presented the TIMELESS trial at last week's European Stroke Organisation Conference 2023, held in Munich, Germany.
He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.
The phase 3 double-blind randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.
The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.
The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.
The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (0.81-1.56; P = .48).
The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group vs 42% in the placebo group (nominal P = .41).
Promising Safety Data
There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group vs 2.3% of the placebo group, a nonsignificant difference.
"The low rate of ICH with TNK at this late time point is very reassuring," Albers said. "We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients," he added.
The secondary endpoint of complete recanalization at 24-hours post-randomization was higher in the TNK group at 76.7% compared with 63.9% in the placebo group (P = .006).
Benefit in M1 Occlusions?
Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).
The percentage of patients with a favorable outcome (mRS 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK vs 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).
But Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.
"We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients," he commented.
"But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis," he added. "But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better."
Timing of TNK
Albers said that there was also information from in the study on the timing of TNK administration.
In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.
"We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center," Albers explained.
"But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo," he reported.
He suggested that this may be due to the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.
"We have learnt a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy," he added.
Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, Greece, said that he thought the trial had shown three important results:
"Firstly, TNK appeared to be safe in this late window in these selected patients — that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy."
Tsivgoulis concluded that these points need to be addressed in future trials.
The TIMELESS trial was funded by Genentech.
European Stroke Organisation Conference 2023. Presented May 24.
Lead image: Jeff Wasserman/Dreamstime
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Cite this: Tenecteplase Late After Stroke Misses Endpoint: TIMELESS - Medscape - May 30, 2023.