Open access Original research

Stroke Vasc Neurol: first published as 10.1136/svn-2023-002820 on 29 January 2024. Downloaded from http://svn.bmj.com/ on February 13, 2024 by guest. Protected by copyright.
Tenecteplase thrombolysis for stroke up
to 24 hours after onset with perfusion
imaging selection: the umbrella phase
IIa CHABLIS-­T randomised clinical trial
Xin Cheng ‍ ‍,1 Lan Hong ‍ ‍,1 Leonid Churilov,2 Longting Lin,3 Yifeng Ling,1
Jin Zhang,4 Jianhong Yang,5 Yu Geng,6 Danhong Wu ‍ ‍,7 Xueyuan Liu,8
Xiaoyu Zhou ‍ ‍,8 Yuwu Zhao,9 Qijin Zhai,10 Liandong Zhao,10 Yangmei Chen,11
Ying Guo,12 Xiaofei Yu,13 Fan Gong,13 Yi Sui ‍ ‍,14 Gang Li ‍ ‍,15 Lumeng Yang,1
Hong-­Qiu Gu ‍ ‍,16 Yilong Wang ‍ ‍,16,17 Mark Parsons,3 Qiang Dong,1 the
CHABLIS-­T collaborators

To cite: Cheng X, Hong L, ABSTRACT

Churilov L, et al. Tenecteplase WHAT IS ALREADY KNOWN ON THIS TOPIC
Background The performance of intravenous
thrombolysis for stroke up tenecteplase in patients who had an acute ischaemic ⇒ Tenecteplase has now been proven to be non-­inferior
to 24 hours after onset with to alteplase, in patients who had an acute ischaemic
stroke with large/medium vessel occlusion or severe
perfusion imaging selection: the stroke within the 4.5-­hour time window. However,
umbrella phase IIa CHABLIS-­T stenosis in an extended time window remains unknown.
We investigated the promise of efficacy and safety of its performance in patients who had an acute stroke
randomised clinical trial. Stroke
different doses of tenecteplase manufactured in China, in with large/medium vessel occlusion or severe steno-
& Vascular Neurology 2024;0.
doi:10.1136/svn-2023-002820 patients who had an acute ischaemic stroke with large/ sis in an extended time window remains unknown.
medium vessel occlusion beyond 4.5-­hour time window. WHAT THIS STUDY ADDS
► Additional supplemental
material is published online only. Methods The CHinese Acute tissue-­Based imaging
⇒ Among patients with anterior large/medium vessel
To view, please visit the journal selection for Lysis In Stroke-­Tenecteplase was an
occlusion and significant penumbral mismatch pre-
online (http://​dx.d​ oi.​org/​10.​ investigator-­initiated, umbrella phase IIa, open-­label, sented within 4.5–24 hours from time of last seen
1136/s​ vn-​2023-0​ 02820). blinded-­endpoint, Simon’s two-­stage randomised clinical well, tenecteplase 0.25 mg/kg and 0.32 mg/kg both
trial in 13 centres across mainland China. Participants provided sufficient promise of efficacy and safety.
Received 4 September 2023 who had salvageable brain tissue on automated perfusion
Accepted 14 December 2023 HOW THIS STUDY MIGHT AFFECT RESEARCH,
imaging and presented within 4.5–24 hours from time
of last seen well were randomised to receive 0.25 mg/ PRACTICE OR POLICY
kg tenecteplase or 0.32 mg/kg tenecteplase, both with ⇒ It seems feasible to extend the time window of intra-
a bolus infusion over 5–10 s. The primary outcome venous tenecteplase thrombolysis to 24 hours after
was proportion of patients with promise of efficacy and last seen well through perfusion imaging selection.
safety defined as reaching major reperfusion without
symptomatic intracranial haemorrhage at 24–48 hours
after thrombolysis. Assessors were blinded to treatment
Trial registration number C​ linicalTrials.​gov Registry
allocation. All participants who received tenecteplase were
(NCT04086147, https://clinicaltrials.gov/ct2/show/​
included in the analysis.
NCT04086147).
Results A total of 86 patients who had an acute
ischaemic stroke identified with anterior large/medium
vessel occlusion or severe stenosis were included in INTRODUCTION
this study from November 2019 to December 2021. All Thrombolysis with alteplase is limited by its
of the 86 patients enrolled either received 0.25 mg/kg short half-­ life and low recanalisation rate
(n=43) or 0.32 mg/kg (n=43) tenecteplase, and were of large vessel occlusion.1 Tenecteplase—a
© Author(s) (or their available for primary outcome analysis. Fourteen out of genetically modified variant of alteplase—
employer(s)) 2024. Re-­use 43 patients in the 0.25 mg/kg tenecteplase group and
has gained increasing interest as an alterna-
permitted under CC BY-­NC. No 10 out of 43 patients in the 0.32 mg/kg tenecteplase
commercial re-­use. See rights tive for alteplase over the past decade. This is
group reached the primary outcome, providing promise
and permissions. Published by of efficacy and safety for both doses based on Simon’s
mainly due to its practical advantages (single
BMJ.
two-­stage design. bolus, rather than 1-­ hour infusion) and a
For numbered affiliations see Discussion Among patients with anterior large/medium number of hypothetical advantages over
end of article.
vessel occlusion and significant penumbral mismatch alteplase, including greater fibrin specificity.2
Correspondence to presented within 4.5–24 hours from time of last seen well, It has been demonstrated that tenecteplase
Dr Qiang Dong; tenecteplase 0.25 mg/kg and 0.32 mg/kg both provided is non-­ inferior to alteplase in unselected
​qiang_​dong163@​163.​com sufficient promise of efficacy and safety. patients who had an ischaemic stroke,3–5

Cheng X, et al. Stroke & Vascular Neurology 2024;0. doi:10.1136/svn-2023-002820 1

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and may be superior to alteplase in acute large vessel The protocol and statistical analysis plan are provided
occlusion.6 Prior tenecteplase trials have recruited acute in online supplemental file.
ischaemic stroke presenting no longer than 6 hours from
symptom onset.3 5 7–15 Thus, the evidence of performance Participants
of tenecteplase beyond 4.5 hours still remains scarce. Patients were considered eligible if they (1) presented
Perfusion imaging selection has been shown to extend with acute ischaemic stroke within 4.5–24 hours from time
the time for thrombolysis,16 though increasing evidence of last seen well and were aged 18 years or older; (2) had a
suggests the optimal dose of tenecteplase in acute stroke clinically significant acute neurological deficit measured
of the Western population is 0.25 mg/kg7 8 10 13 and the by the baseline National Institutes of Health Stroke Scale
Tenecteplase in Stroke Patients Between 4.5 and 24 (NIHSS) score; (3) had a prestroke modified Rankin
Hours (TIMELESS, NCT03785678) trial has reported Scale (mRS) 0–2; (4) fulfilled the ‘dual target’ imaging
that 0.25 mg/kg tenecteplase could improve recanali- criteria, on baseline multimodal CT imaging.
sation compared with placebo.17 The appropriate dose Participants were identified with anterior circula-
in the Chinese patients with acute large/medium vessel tion large/medium vessel occlusion or severe stenosis
occlusion or severe stenosis was unknown when the trial (defined as more than 70% narrowing compared with
started. the adjacent vessel calibre), including the extracranial or
Therefore, our hypothesis is that tenecteplase admin- intracranial internal carotid artery (ICA-­IC/EC), first or
istered to patients who had an ischaemic stroke with a second segment of the middle cerebral artery (MCA-­M1/
favourable penumbral profile on perfusion CT (CTP) M2), and first or second segment of the anterior cere-
between 4.5 and 24 hours from time of last seen well bral artery (ACA-­A1/A2) on CT angiography. Addition-
would be safe and beneficial. ally, a favourable penumbral profile was required on CTP
We conducted the CHinese Acute tissue-­Based imaging imaging using automated real-­time perfusion volumetric
selection for Lysis In Stroke-­Tenecteplase (CHABLIS-­T) software, AutoMIStar (Apollo Medical Imaging Tech-
umbrella phase IIa randomised clinical trial. The goal of nology, Melbourne, Victoria, Australia). A favourable
CHABLIS-­T was to investigate the promise of efficacy and penumbral profile was a hypoperfusion lesion volume
safety of various doses of tenecteplase in Chinese patients (delay time >3 s)18 to infarct core volume (relative cere-
who had an acute ischaemic stroke with large/medium bral blood flow <30%) ratio that was greater than 1.2 with
vessel occlusion or severe stenosis in the anterior circu- an absolute difference of volume greater than 10 mL, and
lation and a favourable penumbral profile between 4.5 an ischaemic core volume less than 70 mL.
and 24 hours from time of last seen well. The tenecteplase Detailed inclusion and exclusion criteria are listed in
used in the trial was produced and approved for treating online supplemental file.
acute myocardial infarction in China and has been used
in Tenecteplase Reperfusion therapy in Acute ischemic Randomisation, intervention and blinding
Cerebrovascular Events (TRACE) trials,5 11 which had Eligible patients were enrolled and randomly assigned in
the same terminal amino acid sequence and different a 1:1 ratio to either dose stratum (0.25 mg/kg, maximum
production process to the tenecteplase made by Boeh- 25 mg, and 0.32 mg/kg, maximum 40 mg) of tenecteplase
ringer (Metalyse) and Genentech (TNKase). (Guangzhou Recomgen Biotech Co), as a bolus over
5–10 s and a following 2 mL bolus of saline for injection.
Randomisation was performed using permuted blocks
through a centralised website by local stroke neurologists.
METHODS Patients were stratified according to time from last seen
Study design well (4.5–12 hours, 12–24 hours) and site of occlusion or
When the trial started, the appropriate dose of severe stenosis (ICA-­IC and MCA-­M1; ICA-­EC, MCA-­M2
tenecteplase in acute stroke, especially in Asian popu- and ACA). The dosage of tenecteplase was open label to
lation, was unknown. Moreover, the bioequivalence of the patients and the clinicians involved in the treatment
tenecteplase produced in China was also unclear. The of participants. Bridging endovascular treatment was
CHABLIS-­T trial adopted a Simon’s two-­stage design for performed according to local guidelines. Guideline-­based
individual dose stratum. The purpose of Simon’s two-­stage intensive care for patients who had an acute ischaemic
design is to determine whether tenecteplase has sufficient stroke with intravenous thrombolysis was recommended
promise against acute stroke with large/medium vessel for every patient. The investigators involved in the subse-
occlusion or severe stenosis in an extended time window quent radiological and clinical evaluation were blinded
in Chinese patients to warrant further investigation. to the allocation.
Under this design, a small group of patients were enrolled
in the first stage, and the activation of the second stage Outcomes
depended on a prespecified number of positive responses The primary outcome was a binary composite of effi-
observed from the first stage. The trial was conducted in cacy and safety, that is, presence of major reperfusion
13 centres across mainland China from November 2019 at the initial catheter angiography or repeated CTP
to December 2021. 4–6 hours in the absence of symptomatic intracerebral

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haemorrhage (sICH) at 24–48 hours after intravenous
tenecteplase. Major reperfusion was defined as the resto-
ration of blood flow of greater than 50% of the involved
territory. For patients not transferred to the catheter labo- Figure 1 Study design: umbrella Simon’s two-­stage design.
ratory after thrombolysis, major reperfusion was consid- TLSW, time from last seen well.
ered as the hypoperfusion lesion volume (delay time >3 s)
of the repeated CTP 4–6 hours decreased to less than
50% of the hypoperfusion lesion volume of the baseline for each stratum was to be rejected if eight or more posi-
CTP. For patients transferred to the catheter laboratory, tive responses were observed in 43 patients. This design
major reperfusion was evaluated as a modified Treatment was to yield a type I error rate of 0.05 and a power of 0.8
In Cerebral Ischemia (mTICI) score 2b/3 at the initial when the true response rate was 25%. Overall, at least 36
catheter angiography. SICH was defined according to the patients were to be enrolled with a maximum enrolment
European Co-­operative Acute Stroke Study-­II criteria.19 of 86 patients equally distributed between the two dose
The secondary radiological efficacy outcomes included strata (figure 1).
recanalisation and infarct growth. The secondary clinical
Statistical analysis
efficacy outcomes included mRS 0–1, mRS 0–2 and mRS
All participants receiving tenecteplase were included in
distribution at 90 days, major neurological improvement
the analysis. For the analysis of the primary endpoint,
at 24–48 hours and change in the NIHSS score within
as described above, if 8 or more out of the 43 patients
24–48 hours. The secondary radiological safety outcomes
reached the primary endpoint within a given stratum,
included parenchymal haematoma type 2 (PH2), sICH19
the respective tenecteplase dose could be considered of
and any ICH at 24–48 hours post-­treatment. The secondary
being sufficient promise in terms of efficacy and safety
clinical safety outcomes included mRS 5–6 at 90 days and
and as a qualified candidate dose for the subsequent
systemic bleeding. Additionally, Barthel Index at 90 days
phase IIb trial.
was also collected. The details of the secondary outcomes
Since the design of this study did not aim to compare
can be found in online supplemental file.
the safety and efficacy of the two tenecteplase doses within
The imaging protocol of multimodal CT at each
the umbrella design, the analyses of secondary outcomes
centre was centrally standardised through careful quality
were descriptive. Secondary outcomes were described
control. All of the imaging results were centrally analysed
using percentages, mean with standard deviation (SD)
in a core laboratory. Baseline multimodal CT imaging was
and median with interquatile range (IQR as appropriate.
reanalysed to make sure that the entry criteria were met.
Normality was tested using Shapiro-­Wilk test.
The radiological outcome measurements were evaluated
In order to inform the design and planning for the
by two independent neuroradiologists, and a third inde-
subsequent phase IIb trial, we also estimated the propor-
pendent rater was consulted in cases of disagreement.
tions of participants achieving primary and secondary
outcomes in patients without severe stenosis in the two
Sample size calculations
tenecteplase dose strata.
The sample size was calculated based on the results
No missing data for baseline information and primary
derived from the Tenecteplase vs Alteplase before Endo-
outcome analysis were observed. Although 13.95% of
vascular Therapy for Ischemic Stroke (EXTEND-­ IA
participants had missing data on Barthel Index, its influ-
TNK) trial,7 where 22% of patients in the intravenous
ence was considered to be minimal since it is a secondary
tenecteplase group and 10% of patients in the intrave-
outcome and the analyses did not involve a comparison
nous alteplase group reached major reperfusion, and
between tenecteplase dose strata.20
1% of patients, respectively, in both groups were found
The statistical analysis was performed on STATA V.15.1
to have sICH. To adopt a conservative approach, for
(StataCorp, College Station, Texas, USA).
each dose stratum within the umbrella design, the null
A data safety monitoring board oversaw the enrolment
hypothesis was that not more than 10% of patients would
of the total 86 patients in this trial.
achieve a positive primary outcome following the respec-
tive dose of tenecteplase, while the alternative hypothesis
was that, not less than 25% of patients would achieve a RESULTS
positive primary outcome following the respective dose From 27 November 2019 to 30 September 2021, a total
of tenecteplase. Sample size estimation using Simon’s of 2193 patients who had an acute ischaemic stroke
two-­stage design was conducted for each dose stratum, presented within 4.5–24 hours from time of last seen
according to which the null hypothesis that the true well at 13 sites, where 86 patients were randomised and
response rate was 10% was tested against a one-­sided alter- received tenecteplase treatment in this trial. The flow
native. In the first stage, 18 patients were to be accrued. diagram of patient selection is shown in figure 2. The
If there were two or fewer positive responses in these 18 preplanned interim analysis according to Simon’s two-­
patients, the dose stratum was to be stopped. Otherwise, stage design was conducted in December 2020, demon-
25 additional patients were to be accrued for a total of strating that each tenecteplase dose stratum had three or
43 patients for each dose stratum. The null hypothesis more patients reaching the primary endpoint, enabling


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Figure 2 Trial profile. CTP, perfusion CT; mRS, modified Rankin Scale

progression to stage 2 in both dose strata. Forty-­three at 90 days. sICH occurred in 4 (9.3%, 95% CI 3.5% to
patients were assigned to each 0.25 mg/kg tenecteplase 22.6%) patients in the 0.25 mg/kg tenecteplase stratum
and 0.32 mg/kg tenecteplase strata, and received corre- and in 4 (9.3%, 95% CI 3.5% to 22.6%) in the 0.32 mg/
sponding tenecteplase treatment as allocated. The base- kg tenecteplase stratum. Details of severe adverse events
line demographic, clinical and imaging characteristics of are displayed in online supplemental table 1.
the two tenecteplase dose strata are listed in table 1. When excluding 13 patients with severe arterial
All of the 86 patients were available for the primary stenosis, the baseline characteristics of the 73 patients
outcome analysis. The primary outcome analysis showed with complete artery occlusion are listed in online supple-
that 14 out of 43 (32.6%, 95% CI 20.2% to 48.0%) mental table 2. The primary outcome was still achieved in
patients in the 0.25 mg/kg tenecteplase stratum and 10 9 out of 35 (25.7%, 95% CI 13.8% to 42.8%) patients in
out of 43 (23.3%, 95% CI 12.9% to 38.3%) patients in the the 0.25 mg/kg tenecteplase stratum and in 9 out of 38
0.32 mg/kg tenecteplase stratum reached major reperfu- (23.7%, 95% CI 12.7% to 39.9%) patients in the 0.32 mg/
sion without sICH after tenecteplase thrombolysis. Addi- kg tenecteplase stratum. Secondary outcomes in patients
tionally, regardless of the occurrence of haemorrhagic with complete artery occlusion of two tenecteplase dose
events, the numbers of patients achieving major reper- strata are shown in online supplemental table 3. Addi-
fusion were 15 (34.9%, 95% CI 22.1% to 50.3%) and 12 tionally, the baseline characteristics of the 52 patients
(27.9%, 95% CI 16.5% to 43.2%) in the 0.25 mg/kg and without bridging endovascular treatment were listed in
0.32 mg/kg dose strata, respectively. online supplemental table 4.
Prespecified secondary efficacy and safety outcomes
are presented in table 2. Recanalisation was attained in
18 (43.9%, 95% CI 29.5% to 59.4%) patients in both DISCUSSION
tenecteplase dose strata (with 41 patients available for In this randomised trial, among 86 patients recruited, 14
analysis each arm) post-­ thrombolysis. Excellent func- out of 43 patients in the 0.25 mg/kg dose stratum and
tional outcome (mRS 0–1) was achieved in 12 (27.9%, 10 out of 43 patients in the 0.32 mg/kg dose stratum
95% CI 16.5% to 43.2%) patients in the 0.25 mg/kg achieved major reperfusion without occurrence of sICH,
tenecteplase stratum and in 21 (48.8%, 95% CI 34.2% to both surpassing the predefined eight-­patient threshold
63.6%) patients in the 0.32 mg/kg tenecteplase stratum of reaching the primary outcome. Therefore, both

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Table 1 Baseline characteristics of the patients randomised
Tenecteplase 0.25 mg/kg Tenecteplase 0.32 mg/kg
(n=43) (n=43)
Age, years 68.3 (13.1) 67.1 (11.5)
Male sex 25 (58.1%) 31 (72.1%)
NIHSS score at randomisation 11 (8–15) 9 (6–13)
Stroke aetiology
 Cardioembolism 15 (34.9%) 7 (16.3%)
 Large artery atherosclerosis 20 (46.5%) 28 (65.2%)
 Undetermined aetiology 8 (18.6%) 8 (18.6%)
Medical history
 Atrial fibrillation 14 (32.6%) 4 (9.3%)
 Hypertension 27 (62.8%) 29 (67.4%)
 Diabetes 12 (27.9%) 16 (37.2%)
 Smoking 15 (34.9%) 25 (58.1%)
 Ischaemic stroke or transient ischaemic attack 6 (14.0%) 5 (11.6%)
TLSW to randomisation
 4.5–12 hours 25 (58.1%) 26 (60.5%)
 12- 24 hours 18 (41.9%) 17 (39.5%)
Witnessed stroke 21 (48.8%) 28 (65.1%)
Transferred to catheter lab 17 (39.5%) 18 (41.9%)
Underwent endovascular treatment 17 (39.5%) 17 (39.5%)
TLSW to hospital arrival, min 497 (310–815) 513 (394–632)
TLSW to initiation of intravenous therapy, min 645 (481–973) 674 (516–808)
Time from hospital arrival to initiation of intravenous therapy, min 130 (99–159) 140 (111–217)
Time from initiation of intravenous thrombolysis to initial 69.0 (45.0–94.5) 62.5 (41.8–93.3)
angiographic assessment, min*
Site of artery occlusion or severe stenosis
 Extracranial segment of intracranial carotid artery 3 (7.0%) 6 (14.0%)
 Intracranial segment of intracranial carotid artery 3 (7.0%) 4 (9.3%)
 First segment of middle cerebral artery 25 (58.1%) 15 (34.9%)
 Second segment of middle cerebral artery 9 (20.9%) 11 (25.6%)
 Anterior cerebral artery 3 (7.0%) 6 (14.0%)
 Tandem occlusion 0 (0.0%) 1 (2.3%)
Vessel severe stenosis at baseline 8 (18.6%) 5 (11.6%)
Hypoperfusion lesion volume at baseline, mL 77 (50–114) 76 (46–120)
Ischaemic core volume at baseline, mL 8 (4–15) 8 (4–19)
Data are mean (SD), n (%), median (IQR).
*Tenecteplase 0.25 mg/kg: n=17; tenecteplase 0.32 mg/kg: n=18.
IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation; TLSW, time from last seen well.

tenecteplase 0.25 mg/kg and tenecteplase 0.32 mg/kg safety profiles.11 However, in another phase IIb trial,
demonstrated sufficient promise of efficacy and safety. two doses of 0.1 and 0.25 mg /kg tenecteplase were
CHABLIS-­T is also one of the few trials that reported compared with alteplase, which showed the higher
the performance of tenecteplase thrombolysis in the dose of tenecteplase was superior to the lower dose and
extended time window. to alteplase for all efficacy outcomes.10 Therefore, we
In TRACE Study, three doses of 0.1, 0.25, 0.32 mg/kg abandoned the lower dose of 0.1 mg/kg tenecteplase,
tenecteplase were compared with 0.9 mg/kg alteplase and examined the promise of efficacy and safety in the
in Chinese patients with acute ischaemic stroke within other higher doses of tenecteplase, that is, 0.25 mg/kg
3 hours from symptom onset, which showed similar and 0.32 mg/kg.


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Table 2 Primary and secondary efficacy and safety outcomes
Tenecteplase 0.25 mg/kg Tenecteplase 0.32 mg/kg
(n=43) (n=43)
Primary outcome* 14 (32.6%) 10 (23.3%)
(major reperfusion without the occurrence of symptomatic ICH)
Secondary outcome
 Efficacy
  
Recanalisation† 18 (43.9%) 18 (43.9%)
  Infarct growth at 3–5 days, mL‡ 23.9 (3.5–55.3) 16.9 (6.7–81.0)
  Major neurological improvement at 24–48 hours§ 7 (17.1%) 8 (18.6%)
  Change in NIHSS score at 24–48 hours compared with baseline§ −1.0 (−6.5, 2.0) 0.0 (−3.0, 2.0)
  mRS score 0–1 at 90 days 12 (27.9%) 21 (48.8%)
  mRS score 0–2 at 90 days 20 (46.5%) 26 (60.5%)
  mRS score at 90 days
   
0 7 (16.3%) 8 (18.6%)
   
1 5 (11.6%) 13 (30.2%)
   
2 8 (18.6%) 5 (11.6%)
   
3 5 (11.6%) 3 (7.0%)
   
4 7 (16.3%) 7 (16.3%)
   
5 5 (11.6%) 5 (11.6%)
   
6 6 (14.0%) 2 (4.7%)
 Safety
  
Symptomatic ICH 4 (9.3%) 4 (9.3%)
Any ICH
   21 (48.8%) 13 (30.2%)
  Parenchymal haematoma type 2 5 (11.6%) 1 (2.3%)
  mRS score 5–6 at 90 days 11 (25.6%) 7 (16.3%)
   Systematic haemorrhage 3 (7.0%) 1 (2.3%)
 Barthel Index at 90 days¶ 95.0 (50.0–100.0) 95.0 (47.5–100.0)
Data are n (%), median (IQR).
*Major reperfusion was assessed at the initial catheter angiography or repeated CTP 4–6 hours and symptomatic ICH was assessed at 24–
48 hours after intravenous tenecteplase treatment.
†Tenecteplase 0.25 mg/kg: n=41; tenecteplase 0.32 mg/kg: n=41.
‡Tenecteplase 0.25 mg/kg: n=36; tenecteplase 0.32 mg/kg: n=41.
§Tenecteplase 0.25 mg/kg: n=41.
¶Tenecteplase 0.25 mg/kg: n=33; tenecteplase 0.32 mg/kg: n=41.
CTP, perfusion CT; ICH, intracranial haemorrhage; IQR, interquartile range; mRS, modified Rankin Scale; NIHSS, National Institutes of Health
Stroke Scale.

Prompt reperfusion is of great importance for patients possible explanation is that the time window of reperfu-
who had an acute ischaemic stroke with large vessel sion assessment in CHABLIS-­T was around 60 min for
occlusion. Previous studies have shown that tenect- patients transferred for catheter angiography (similar to
eplase, as a single bolus administration, could achieve EXTEND-­IA TNK), and 4–6 hours for patients not trans-
more rapid and substantial reperfusion compared with ferred (60% of CHABLIS-­T participants).7 8 Apart from
alteplase.21–23 The recently reported TIMELESS trial the time window, the imaging modality of reperfusion
(NCT03785678) has also reported a higher rate of reca- assessments may also play a part, since reperfusion status
nalisation at 24 hours in the tenecteplase group than was mainly assessed through repeated perfusion imaging
the placebo group.17 The current trial showed that both rather than catheter angiography in the CHABLIS-­ T
0.25 mg/kg and 0.32 mg/kg tenecteplase dose groups trial, which was the opposite to the EXTEND-­IA TNK
could reach a substantial reperfusion rate of around 30%, trials.7 8 However, reperfusion status assessed through
compared with the 20% in the EXTEND-­IA TNK trials. perfusion imaging has been proven to have at least equiv-
One possible explanation is that we included medium alent predictive ability for functional outcome compared
vessel occlusion or severe stenosis, which could have with mTICI scores in catheter angiography.24 25 As for
higher reperfusion rate treated by tenecteplase. Another the safety concerns, we did not observe a higher rate of

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sICH or PH2 in the higher dose stratum. However, the considered to be of sufficient promise. These results are
percentages of haemorrhagic transformation (including in accordance with those of EXTEND-­IA TNK Part2 trial,
symptomatic and asymptomatic) in this trial were notably where 0.4 mg/kg tenecteplase had similar effect on reper-
higher than those of randomised controlled trials with fusion and other outcomes in patients with large vessel
patients with large vessel occlusion treated with intrave- occlusions, compared with 0.25 mg/kg tenecteplase.8
nous thrombolysis.7–10 16 26 Since the thrombolytic time Third, the sample size of this study was underpowered to
windows of prior trials range from ≤4.5 hours to ≤9 hours make reliable conclusions regarding the effect of tenect-
after last seen well, the higher risk of haemorrhagic trans- eplase on long-­ term functional outcomes (mRS at 90
formation in this trial can be partly explained by the days). Further, the primary outcome in this dose-­finding
longer onset-­to-­reperfusion time.27 Additionally, though study was different from that of phase III trials, making
patients in CHABLIS-­T have been selected with benign direct comparisons unreliable. However, the imaging
perfusion profiles, they may exhibit risk factors of sICH composite primary outcome of both efficacy and safety is
that could not be detected simply by automatically post-­ objective, immediate and straightforward, and more suit-
processed perfusion imaging (ie, larger volumes of very able for an adaptive sample size re-­estimation early phase
low cerebral blood flow),28 which should be further II design. Moreover, reperfusion without sICH usually
explored by post-­hoc analysis. Despite the higher sICH translates to a good functional outcome at 90 days.
rates, both doses of 0.25 mg/kg and 0.32 mg/kg tenect- Fourth, the tenecteplase used in the trial is manufactured
eplase appear to be of sufficient promise in patients who locally, which limits its generalisability to other countries.
had an acute ischaemic stroke with large/medium vessel Last but not least, the sample size calculation was based
occlusion or severe stenosis in the extended time window. on a trial with shorter thrombolysis-­to-­reperfusion assess-
Though the design of the study was not driven by the ment time, while the reperfusion rate might be higher in
direct comparison between 0.25 mg/kg and 0.32 mg/kg CHABLIS-­T than the assumed rate. However, the number
tenecteplase, more patients in the 0.25 mg/kg tenect- of patients needed would be smaller than the 86 patients
eplase dose stratum reached the primary outcome but if higher reperfusion rate had been considered. There-
failed to achieve 3-­month mRS 0–1 or 0–2, compared with fore, CHABLIS-­T, with the current sample size, had suffi-
patients in the 0.32 mg/kg dose stratum. This discrepancy cient power to detect the promise of efficacy and safety of
may be explained by the higher baseline NIHSS, higher tenecteplase.
prevalence of cardioembolic stroke and higher rate of In conclusion, among patients with large/medium
PH2 in the 0.25 mg/kg dose stratum. vessel occlusion or severe stenosis in the anterior circula-
In the CHABLIS-­T trial, we included both patients with tion and a favourable penumbral profile presenting within
complete large/medium vessel occlusion as well as those 4.5–24 hours from time of last seen well, both tenecteplase
with severe stenosis. The reason why patients with severe 0.25 mg/kg and 0.32 mg/kg doses demonstrated suffi-
stenosis were also eligible for this trial is that a consid- cient promise to achieve substantial reperfusion without
erable number of acute ischaemic stroke events in East sICH. Currently, other tenecteplase-­ related thrombo-
Asian population are due to acute in-­ situ thrombosis lytic randomised controlled trials in patients with large
with underlying chronic stenosis resulting from intracra- vessel occlusion, including TIMELESS (NCT03785678),
nial large artery atherosclerosis. Such patients were also Extending the Time Window for Tenecteplase by Effec-
candidates for acute reperfusion therapy and as such tive Reperfusion in Patients With Large Vessel Occlu-
excluding patients with severe stenosis would undermine sion (ETERNAL-­ LVO, NCT04454788) and TRACE
the generalisability of this trial. Notably, when excluding III (NCT05141305), choose 0.25 mg/kg as the experi-
patients with severe stenosis, the primary outcome was mental tenecteplase dosage. Additionally, Tenecteplase vs
still achieved in more than seven patients of each dose alteplase for the management of acute ischaemic stroke
stratum in patients with complete artery occlusion. in Norway (NOR-­ TEST 2) trial failed to demonstrate
A novel feature of CHABLIS-­ T trial was using the superiority of 0.40 mg/kg tenecteplase compared with
umbrella Simon’s two-­stage trial design in order to inves- alteplase with a higher risk of bleeding events and worse
tigate the clinical promise of two doses of tenecteplase. functional outcomes in moderate and severe stroke.13
Though not ever applied in stroke previously, Simon’s Based on the results of CHABLIS-­T, TRACE and other
two-­stage design is acknowledged as a simple and effec- completed tenecteplase-­ related randomised controlled
tive dose selection method allowing modest sample size,29 trials, a subsequent phase IIb trial, CHinese Acute tissue-­
especially in oncology trials. Based imaging selection for Lysis In Stroke-­Tenecteplase
The study has the following limitations. First of all, the II (CHABLIS-­ T II) trial, is ongoing to investigate the
study design did not have an alteplase control group. performance of tenecteplase 0.25 mg/kg in comparison
However, the novel design (for a stroke trial) was aimed with best medical treatment (NCT04516993). The recent
for dose finding rather than treatment comparison. reported TIMELESS trial did not show superiority of
Second, the design of this trial does not enable a direct tenecteplase in improvement of 3-­month outcome though
comparison between 0.25 mg/kg and 0.32 mg/kg tenect- recanalisation rate was improved, which is probably due
eplase. With both dose strata reaching the predefined to the strong clinical benefit of endovascular treatment.17
threshold for the primary outcome, both doses can be Therefore, CHABLIS-­T II, together with other ongoing


Cheng X, et al. Stroke & Vascular Neurology 2024;0. doi:10.1136/svn-2023-002820 7
 Open access

Stroke Vasc Neurol: first published as 10.1136/svn-2023-002820 on 29 January 2024. Downloaded from http://svn.bmj.com/ on February 13, 2024 by guest. Protected by copyright.
trials, may help to further explore the optimal clinical informed consent was acquired from all the eligible patients or their legal proxies
setting where the recanalisation benefit of tenecteplase before randomisation.
Provenance and peer review Not commissioned; externally peer reviewed.
can be maximally translated into clinical benefit.
Data availability statement Data are available upon reasonable request. Readers
should contact the corresponding author (at ​qiang_​dong163@​163.​com) if they wish
Author affiliations to enquire about data sharing.
1
Department of Neurology, National Center for Neurological Disorders, National
Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan Supplemental material This content has been supplied by the author(s). It has
University, Shanghai, China not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
2
Melbourne Medical School, The Royal Melbourne Hospital, University of Melbourne, peer-­reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
Parkville, Victoria, Australia
3 responsibility arising from any reliance placed on the content. Where the content
University of New South Wales South Western Sydney Clinical School, Ingham
includes any translated material, BMJ does not warrant the accuracy and reliability
Institute for Applied Medical Research, Department of Neurology, Liverpool Hospital, of the translations (including but not limited to local regulations, clinical guidelines,
Sydney, New South Wales, Australia terminology, drug names and drug dosages), and is not responsible for any error
4
Department of Neurology, the First Hospital of Shanxi Medical University, Taiyuan, and/or omissions arising from translation and adaptation or otherwise.
China
5 Open access This is an open access article distributed in accordance with the
Department of Neurology, Ningbo First Hospital, Ningbo, China
6 Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial
permits others to distribute, remix, adapt, build upon this work non-­commercially,
People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College),
and license their derivative works on different terms, provided the original work is
Hangzhou, China properly cited, appropriate credit is given, any changes made indicated, and the use
7
Department of Neurology, Shanghai Fifth People's Hospital, Fudan University, is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Shanghai, China
8
Department of Neurology, Shanghai Tenth People's Hospital, Tongji University ORCID iDs
School of Medicine, Shanghai, China Xin Cheng http://orcid.org/0000-0001-7816-0547
9
Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Lan Hong http://orcid.org/0000-0002-4002-4627
Jiao Tong University School of Medicine, Shanghai, China Danhong Wu http://orcid.org/0000-0002-1132-6669
10
Department of Neurology, Xuzhou Medical University Affiliated Hospital of Huaian, Xiaoyu Zhou http://orcid.org/0000-0002-3947-1788
Huaian, China Yi Sui http://orcid.org/0000-0002-2898-7877
11
Department of Neurology, The Second Affiliated Hospital of Chongqing Medical Gang Li http://orcid.org/0000-0003-1009-2124
University, Chongqing, China Hong-­Qiu Gu http://orcid.org/0000-0003-1608-1856
12 Yilong Wang http://orcid.org/0000-0002-3267-0039
Department of Neurology, Pu'er People's Hospital, Pu'er, China
13
Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of
Traditional Chinese Medicine, Shanghai, China
14
Department of Neurology, Shenyang First People's Hospital, Shenyang Medical
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