Results from the TIMELESS trial represent “fantastic news” on the safety of intravenous tenecteplase in selected late-window stroke patients, despite the drug failing to meet its prespecified primary and secondary efficacy endpoints.
That is according to Gregory Albers (Stanford Medicine, Stanford, USA), who delivered these data for the first time at the European Stroke Organisation Conference (ESOC; 24–26 May, Munich, Germany).
The Phase 3, double-blinded, randomised, placebo-controlled TIMELESS study sought to investigate if tenecteplase—administered in ischaemic stroke patients with large vessel occlusions and a favourable perfusion-imaging profile, presenting between 4.5 and 24 hours after time last known well—would improve clinical outcomes, as measured by modified Rankin scale (mRS) scores at day 90.
Patients meeting the eligibility criteria of an internal carotid artery (ICA) occlusion or an M1/M2 occlusion in the middle cerebral artery, and favourable perfusion imaging, were randomised 1:1 to receive either intravenous thrombolysis (IVT) with tenecteplase (0.25mg/kg; maximum 25mg) or a placebo drug. The study enrolled a total of 458 patients.
Regarding the primary efficacy endpoint in TIMELESS’ intention-to-treat analysis, Albers reported that some themes favouring tenecteplase were observed, in that there was a trend toward more patients having an excellent outcome when given the drug. However, these signals were not maintained across the full spectrum of stroke outcomes, he continued, and no significant difference was seen between the two groups in terms of the overall odds of achieving less disability at 90 days.
In addition to comparable 0–2 mRS rates of 46% and 42% in the tenecteplase and placebo groups, respectively, the speaker highlighted an increased rate of complete recanalisation at 24 hours with tenecteplase (77%) versus placebo (64%)—as per the trial’s secondary endpoints.
Arriving at what he described as “fantastic news”, Albers then disclosed safety outcomes from the trial. He said that “no hint of safety concern” was observed despite a treatment window of 24 hours, reporting low rates of symptomatic/any intracranial haemorrhage (ICH), serious adverse event, or death, with no significant discrepancies between the tenecteplase and placebo groups.
According to Albers, TIMELESS therefore constitutes the first time tenecteplase—or any thrombolytic drug for ischaemic stroke—has been shown to produce no safety-related concerns across “a very extended time window” (treatment was given up to 24 hours since last known well) in a large-scale clinical stroke trial.
Briefly touching on “interesting findings” from analyses of the study’s subgroups, the speaker said that, although the average time from drug administration to groin puncture was lower than he and his co-investigators would ideally have wanted, longer dwell times yielded “no apparent advantage” in terms of patient outcomes. And, based on common odds ratios, patients in whom mechanical thrombectomy was planned appeared to have a marginally better treatment effect when they received tenecteplase, while those without a planned thrombectomy had a trend towards slightly better outcomes when treated with placebo.
Another finding shared by Albers was that older patients, and patients with higher National Institutes of Health stroke scale (NIHSS) scores, did not appear to experience a reduced likelihood of a favourable treatment effect when compared to younger patients and those with lower NIHSS scores—and there was no sign that tenecteplase was less effective when administered later on in the 4.5-to-24-hour treatment window either.
Prior to concluding, the speaker also highlighted what he feels may be the “most provocative finding” from TIMELESS: the fact that, in a large, prespecified subgroup of M1 occlusion stroke patients, there was a substantial trend towards greater treatment responses in those who received tenecteplase versus placebo, as compared to stroke patients with M2 or ICA occlusions. However, he noted that this aspect of the trial was an exploratory, hypothesis-generating analysis and, as such, “no formal conclusions should be drawn from these data” without further investigations.
At the close of his talk, Albers reiterated that, in this population of late-window patients with favourable perfusion imaging profiles, no safety concerns were identified in the 4.5-to-24-hour treatment window, adding: “Most importantly, [based on TIMELESS], we can say that an intravenous thrombolytic can be safely given in this patient population.”