PDF: CHABLIS-T
(2024)Objective
To investigate the promise of efficacy and safety of 0.25mg/kg and 0.32mg/kg tenecteplase in acute ischaemic stroke with large/medium vessel occlusion beyond 4.5 hours using perfusion imaging selection.
Study Summary
• Recanalisation rate was 43.9% in both dose groups
• mRS 0-1 at 90 days: 27.9% (0.25mg/kg) vs 48.8% (0.32mg/kg); mRS 0-2: 46.5% vs 60.5%
• sICH rate was 9.3% in both groups
• Any ICH: 48.8% (0.25mg/kg) vs 30.2% (0.32mg/kg)
Intervention
Tenecteplase 0.25mg/kg vs Tenecteplase 0.32mg/kg
Inclusion Criteria
Acute ischaemic stroke 4.5-24h from last seen well, age >=18, anterior large/medium vessel occlusion or severe stenosis on CTA, favourable penumbral mismatch on CTP (mismatch ratio >1.2, absolute difference >10mL, core <70mL), prestroke mRS 0-2
Study Design
Arms: Tenecteplase 0.25mg/kg (n=43) vs Tenecteplase 0.32mg/kg (n=43)
Patients per Arm: 43 per arm (86 total)
Outcome
• Recanalisation: 43.9% in both arms
• mRS 0-2 at 90 days: 46.5% vs 60.5%
• sICH: 9.3% in both arms
• Both doses demonstrated sufficient promise of efficacy and safety per Simon's two-stage design
Bottom Line
Among patients with anterior large/medium vessel occlusion and significant penumbral mismatch presenting 4.5-24 hours from last seen well, both tenecteplase 0.25mg/kg and 0.32mg/kg demonstrated sufficient promise of efficacy and safety, with major reperfusion without sICH achieved in 32.6% and 23.3% respectively, both exceeding the predefined threshold.
Major Points
- Both 0.25mg/kg (14/43, 32.6%) and 0.32mg/kg (10/43, 23.3%) tenecteplase exceeded the predefined efficacy/safety threshold (8/43) for major reperfusion without sICH
- Recanalisation rate was identical at 43.9% in both dose groups
- The 0.32mg/kg group had better 90-day functional outcomes (mRS 0-1: 48.8% vs 27.9%) despite lower primary outcome rates, possibly due to lower baseline NIHSS and less cardioembolic stroke
- sICH rates were equal at 9.3% in both groups, but any ICH was higher in the 0.25mg/kg group (48.8% vs 30.2%)
- Reperfusion rates (~30%) were higher than EXTEND-IA TNK (~20%), possibly due to inclusion of medium vessel occlusion/severe stenosis and longer reperfusion assessment windows
- First stroke trial to use umbrella Simon's two-stage design for dose finding
- Results supported selection of 0.25mg/kg for the subsequent phase IIb CHABLIS-T II trial
Study Design
- Study Type
- Phase IIa, umbrella, open-label, blinded-endpoint, Simon's two-stage randomised clinical trial
- Randomization
- Yes
- Blinding
- Open-label treatment, blinded endpoint assessment (PROBE)
- Sample Size
- 86
- Follow-up
- 90 days
- Centers
- 13
- Countries
- China
Primary Outcome
Definition: Major reperfusion (assessed at initial catheter angiography or repeated CTP at 4-6 hours) in the absence of symptomatic intracerebral haemorrhage (sICH) at 24-48 hours after thrombolysis
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 14/43 (32.6%) | 10/43 (23.3%) | - (0.25mg/kg: 20.2%-48.0%; 0.32mg/kg: 12.9%-38.3%) | Not applicable (Simon's two-stage design threshold-based) |
Limitations & Criticisms
- No alteplase or placebo control group -- dose-finding design only
- Not powered for direct comparison between the two tenecteplase doses
- Small sample size (n=86) insufficient for reliable conclusions on long-term functional outcomes
- Open-label dosing (though endpoints were blinded)
- Tenecteplase manufactured locally in China (Guangzhou Recomgen) -- different production process from Boehringer/Genentech, limiting international generalisability
- Higher rates of haemorrhagic transformation than prior LVO thrombolysis trials, possibly due to longer time window
- Imbalanced baseline characteristics between groups (higher NIHSS and AF in 0.25mg/kg group)
Citation
Cheng X, Hong L, Churilov L, et al. Stroke Vasc Neurol. 2024;0. doi:10.1136/svn-2023-002820