CHABLIS-T
CHinese Acute tissue-Based imaging selection for Lysis In Stroke-Tenecteplase
Year of Publication: 2024
Authors: Cheng X, Hong L, Churilov L, ..., Dong Q
Journal: Stroke & Vascular Neurology
Citation: Cheng X, Hong L, Churilov L, et al. Stroke Vasc Neurol. 2024;0. doi:10.1136/svn-2023-002820
Link: https://doi.org/10.1136/svn-2023-002820
PDF: https://svn.bmj.com/content/svnbmj/early...002820.full.pdf
PDF: Clinical Question
Can tenecteplase achieve safe reperfusion in large vessel occlusion strokes 4.5-24 hours after onset using perfusion imaging selection?
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
Design
Study Type: Phase IIa, umbrella, open-label, blinded-endpoint, Simon's two-stage randomised clinical trial
Randomization: 1
Blinding: Open-label treatment, blinded endpoint assessment (PROBE)
Allocation: 1:1 to 0.25mg/kg or 0.32mg/kg tenecteplase
Enrollment Period: 27 November 2019 to 30 September 2021
Follow-up Duration: 90 days
Centers: 13
Countries: China
Sample Size: 86
Analyzed: 86
Analysis: Simon's two-stage design with predefined thresholds; descriptive analysis of secondary outcomes
Power Calculation: Null hypothesis: <=10% response rate; alternative: >=25% response rate. Stage 1: 18 patients, stop if <=2 responses. Stage 2: 25 additional (total 43). Reject null if >=8 responses. Type I error 0.05, power 0.80.
Registration: NCT04086147
Inclusion Criteria
- Acute ischaemic stroke within 4.5-24 hours from last seen well
- Age >= 18 years
- Clinically significant acute neurological deficit on baseline NIHSS
- Prestroke mRS 0-2
- Anterior large/medium vessel occlusion or severe stenosis (>70%) on CTA (ICA-IC/EC, MCA-M1/M2, ACA-A1/A2)
- Favourable penumbral mismatch on CTP: mismatch ratio >1.2, absolute difference >10mL, ischaemic core <70mL
Exclusion Criteria
- Detailed exclusion criteria listed in supplemental file
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Label | Tenecteplase 0.25mg/kg (n=43) | Tenecteplase 0.32mg/kg (n=43) |
| Age | 68.3 (13.1) | 67.1 (11.5) |
| Male sex | 58.1% | 72.1% |
| NIHSS score | 11 (IQR 8-15) | 9 (IQR 6-13) |
| Cardioembolism | 34.9% | 16.3% |
| Large artery atherosclerosis | 46.5% | 65.2% |
| Undetermined aetiology | 18.6% | 18.6% |
| Atrial fibrillation | 32.6% | 9.3% |
| Hypertension | 62.8% | 67.4% |
| Diabetes | 27.9% | 37.2% |
| Smoking | 34.9% | 58.1% |
| Prior ischaemic stroke or TIA | 14.0% | 11.6% |
| TLSW 4.5-12h | 58.1% | 60.5% |
| TLSW 12-24h | 41.9% | 39.5% |
| Witnessed stroke | 48.8% | 65.1% |
| Underwent endovascular treatment | 39.5% | 39.5% |
| TLSW to hospital arrival (min) | 497 (IQR 310-815) | 513 (IQR 394-632) |
| TLSW to IV therapy (min) | 645 (IQR 481-973) | 674 (IQR 516-808) |
| MCA-M1 occlusion | 58.1% | 34.9% |
| Severe stenosis at baseline | 18.6% | 11.6% |
| Hypoperfusion volume (mL) | 77 (IQR 50-114) | 76 (IQR 46-120) |
| Ischaemic core volume (mL) | 8 (IQR 4-15) | 8 (IQR 4-19) |
Arms
| Field | Tenecteplase 0.25mg/kg | Tenecteplase 0.32mg/kg |
|---|---|---|
| N | 43 | 43 |
| Intervention | Tenecteplase 0.25mg/kg (max 25mg) IV bolus over 5-10s | Tenecteplase 0.32mg/kg (max 40mg) IV bolus over 5-10s |
| Duration | Single bolus | Single bolus |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| 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 | Primary | 14/43 (32.6%) | 10/43 (23.3%) | Both exceeded predefined threshold of 8/43 | Not applicable (Simon's two-stage design threshold-based) |
| Recanalisation | Secondary | 18/41 (43.9%) | 18/41 (43.9%) | ||
| mRS 0-1 at 90 days | Secondary | 12/43 (27.9%) | 21/43 (48.8%) | ||
| mRS 0-2 at 90 days | Secondary | 20/43 (46.5%) | 26/43 (60.5%) | ||
| Major neurological improvement at 24-48h | Secondary | 7/41 (17.1%) | 8/43 (18.6%) | ||
| Change in NIHSS at 24-48h | Secondary | -1.0 (IQR -6.5, 2.0) | 0.0 (IQR -3.0, 2.0) | ||
| Infarct growth at 3-5 days (mL) | Secondary | 23.9 (IQR 3.5-55.3) | 16.9 (IQR 6.7-81.0) | ||
| Barthel Index at 90 days | Secondary | 95.0 (IQR 50.0-100.0) | 95.0 (IQR 47.5-100.0) | ||
| Symptomatic ICH (ECASS-II) | Safety | 4/43 (9.3%) | 4/43 (9.3%) | ||
| Any ICH | Safety | 21/43 (48.8%) | 13/43 (30.2%) | ||
| Parenchymal haematoma type 2 (PH2) | Safety | 5/43 (11.6%) | 1/43 (2.3%) | ||
| mRS 5-6 at 90 days | Safety | 11/43 (25.6%) | 7/43 (16.3%) | ||
| Systemic haemorrhage | Safety | 3/43 (7.0%) | 1/43 (2.3%) | ||
| sICH (0.25mg/kg) | Adverse | 9.3% | |||
| sICH (0.32mg/kg) | Adverse | 9.3% | |||
| Any ICH (0.25mg/kg) | Adverse | 48.8% | |||
| Any ICH (0.32mg/kg) | Adverse | 30.2% | |||
| PH2 (0.25mg/kg) | Adverse | 11.6% | |||
| PH2 (0.32mg/kg) | Adverse | 2.3% | |||
| Death (0.25mg/kg) | Adverse | 14.0% | |||
| Death (0.32mg/kg) | Adverse | 4.7% | |||
Subgroup Analysis
Excluding 13 patients with severe stenosis: primary outcome still achieved in 9/35 (25.7%) for 0.25mg/kg and 9/38 (23.7%) for 0.32mg/kg, both still exceeding the threshold.
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)
Funding
National Key R&D Program of China (2017YFC1308201), Clinical Research Plan of SHDC (SHDC2020CR1041B), Shanghai Municipal Key Clinical Specialty (shslczdzk06102). Guangzhou Recomgen Biotech Co supplied investigational product and insurance.
Based on: CHABLIS-T (Stroke & Vascular Neurology, 2024)
Authors: Cheng X, Hong L, Churilov L, ..., Dong Q
Citation: Cheng X, Hong L, Churilov L, et al. Stroke Vasc Neurol. 2024;0. doi:10.1136/svn-2023-002820
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