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OPTION

Tenecteplase for Acute Non–Large Vessel Occlusion in the Extended Time Window (OPTION): A Randomized Clinical Trial

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Year of Publication: 2026

Authors: Gaoting Ma, Ran Mo, Yingting Zuo, ..., for the OPTION Investigators

Journal: JAMA

Citation: JAMA. 2026. doi:10.1001/jama.2026.0210

Link: https://doi.org/10.1001/jama.2026.0210

Clinical Question

Does intravenous tenecteplase (0.25 mg/kg) administered 4.5 to 24 hours after stroke onset improve functional outcomes in patients with non-large vessel occlusion acute ischemic stroke and salvageable brain tissue on CT perfusion imaging?

Bottom Line

IV tenecteplase at 4.5–24 hours significantly increased the rate of excellent functional outcome (mRS 0–1) at 90 days compared with standard medical treatment (43.6% vs 34.2%; RR 1.28; P=.02; NNT=11). The ordinal mRS shift, 24-hour reperfusion, and early clinical response all favored tenecteplase. However, symptomatic ICH was significantly higher (2.8% vs 0%; P=.004), and 90-day mortality was numerically but not significantly increased (5.0% vs 3.2%; P=.28). This is the first trial to demonstrate benefit of late-window thrombolysis specifically in non-LVO stroke selected by perfusion imaging, complementing TRACE-III (LVO without thrombectomy access) and HOPE (mixed population with alteplase).

        Major Points
        OPTION was a multicenter, randomized, open-label, blinded-endpoint trial at 48 Chinese centers enrolling 566 patients with non-LVO AIS and CTP-confirmed salvageable tissue at 4.5–24 hours (June 2023–August 2025)
Primary endpoint met: mRS 0–1 at 90 days in 43.6% tenecteplase vs 34.2% control (RR 1.28; 95% CI 1.04–1.57; P=.02; adjusted RR 1.32; P=.007; NNT=11)
Ordinal mRS shift favored tenecteplase (common OR 1.39; 95% CI 1.04–1.86; P=.03); functional independence (mRS 0–2) was 62.8% vs 55.3% (RR 1.14; P=.07, nominally nonsignificant)
24-hour reperfusion: 37.7% vs 28.8% (RR 1.31; P=.03); early clinical response at 24 h: 11.4% vs 5.0% (RR 2.30; P=.007)
Symptomatic ICH (Heidelberg): 2.8% vs 0% (RD 2.85%; P=.004); 2 of 21 patients with mismatch inconsistency (CT hypodensity > CTP core) developed sICH
90-day mortality: 5.0% vs 3.2% (RR 1.57; P=.28, not significant); moderate/severe systemic bleeding: 0.7% in both groups
Most common qualifying arteries: M2 (31.6%), anterior cerebral artery (15.2%), posterior cerebral artery (13.8%), M3-M4 (7.6%); 23.3% had stenosis without occlusion
Median onset-to-randomization was 12.0 hours; 32% were wake-up strokes; median NIHSS 7 (IQR 5–9); median ischemic core volume 0–1 mL (very small cores)
No treatment effect heterogeneity across 7 prespecified subgroups (age, time window, NIHSS, circulation, qualifying artery, glucose, SBP) or post hoc stroke etiology subgroup
Post hoc analysis of patients meeting ESCAPE-MeVO/DISTAL criteria (68.2%): mRS 0–1 42.6% vs 33.0% (RR 1.29; P=.054, approaching significance)

      

Design

Study Type: Multicenter, randomized, open-label, blinded-endpoint (PROBE) clinical trial

Randomization: 1

Blinding: Open-label treatment assignment. Blinded outcome assessment: mRS at 90 days obtained by structured telephone interview by blinded assessors; audio recordings reviewed by independent blinded neurologist. Imaging adjudicated at independent core lab.

Enrollment Period: June 2, 2023 to August 4, 2025 (final follow-up October 28, 2025)

Follow-up Duration: 90 days

Centers: 48

Countries: China

Sample Size: 566

Analysis: Intention-to-treat (all randomized without consent withdrawal). Primary: modified Poisson regression with robust error estimation for RR; post hoc RD via generalized linear model. Secondary ordinal mRS: ordinal logistic regression (proportional odds confirmed). Non-normal continuous outcomes: win-ratio approach. Prespecified adjusted analyses for age, baseline NIHSS, circulation, and onset-to-randomization time. Subgroup interactions tested for 7 prespecified + 1 post hoc variable. Sensitivity: GEE with center as cluster. Per-protocol analysis performed. Originally powered for 568 patients (80% power, 2-sided α=.048 after planned interim), but interim analysis was not conducted due to rapid enrollment; no α was spent. SAS 9.4 and R 4.1.1.

Inclusion Criteria

Age ≥18 years
Prestroke mRS 0 or 1
Acute ischemic stroke treatable 4.5–24 hours after time last seen well
NIHSS 6–25, or NIHSS 4–5 with disabling deficit (hemianopia, aphasia, or loss of hand function)
Non-large vessel occlusion (no ICA, M1, or vertebrobasilar artery occlusion)
CT perfusion mismatch: ischemic core <50 mL (rCBF <30%), mismatch ratio ≥1.2, mismatch volume ≥10 mL (Tmax >6 sec)
No planned endovascular thrombectomy

Exclusion Criteria

Large vessel occlusion (ICA, M1, or vertebrobasilar artery)
Planned endovascular thrombectomy during screening
Platelet count <100 × 10⁹/L
Serum creatinine >220 µmol/L
Standard thrombolysis contraindications
Additional criteria detailed in eMethods 1 (Supplement 3)

Arms

Field	Control	Tenecteplase 0.25 mg/kg
Intervention	Antiplatelet therapy and standard care per Chinese AIS Guidelines (2018, updated 2023). Rescue thrombectomy permitted for clinical deterioration per local clinician judgment.	IV tenecteplase 0.25 mg/kg (maximum 25 mg) bolus over 5–10 seconds immediately after randomization. Rescue thrombectomy permitted for clinical deterioration.
Duration	90 days follow-up	90 days follow-up

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Excellent functional outcome defined as mRS 0 or 1 at 90 days, assessed by blinded telephone interview with independent audio review	Primary	97/284 (34.2%)	123/282 (43.6%)	1.28 (adjusted 1.32)	.02 (adjusted .007)
Ordinal mRS distribution at 90 days	Secondary				.03
Functional independence (mRS 0–2) at 90 days	Secondary	157/284 (55.3%)	177/282 (62.8%)	1.14 (95% CI 0.99–1.30)	.07 (nominally nonsignificant; adjusted RR 1.16, P=.03)
Reperfusion at 24 hours (>90% Tmax >6s volume reduction)	Secondary	76/264 (28.8%)	95/252 (37.7%)	1.31 (95% CI 1.02–1.68)	.03
Early clinical response at 24 hours (NIHSS reduction ≥8 or NIHSS ≤1)	Secondary	14/282 (5.0%)	32/280 (11.4%)	2.30 (95% CI 1.26–4.22)	.007
Infarct volume at 24 hours (mL)	Secondary	6.2 (IQR 1.2–19.9)	5.6 (IQR 1.2–19.8)		.87 (not significant)
NIHSS change at 7 days	Secondary	−2 (IQR −4 to −1)	−3 (IQR −5 to −1)		.16 (not significant)
EQ-5D-5L at 90 days	Secondary	0.9 (IQR 0.6–1.0)	0.9 (IQR 0.6–1.0)		.83 (not significant)
Symptomatic ICH within 36 h (Heidelberg)	Adverse	0/284 (0%)	8/281 (2.8%)		.004 (Fisher exact)
Moderate or severe systemic bleeding within 90 d (GUSTO)	Adverse	2/284 (0.7%)	2/281 (0.7%)	1.01 (95% CI 0.14–7.12)	.99
Death within 90 days	Adverse	9/284 (3.2%)	14/281 (5.0%)	1.57 (95% CI 0.69–3.57)	.28

Subgroup Analysis

No evidence of treatment effect heterogeneity across 7 prespecified subgroups: age (<65 vs ≥65), NIHSS (<10 vs ≥10), circulation (anterior vs posterior), onset-to-randomization (4.5–9 h vs >9–24 h), qualifying artery, serum glucose (<100 vs ≥100 mg/dL), and SBP (≤140 vs >140 mm Hg). Post hoc stroke etiology subgroup also showed no interaction (all P for interaction >.35). Posterior circulation showed a numerically larger effect (RR 1.59; 95% CI 1.06–2.40). Post hoc ESCAPE-MeVO/DISTAL-eligible subgroup (68.2%): 42.6% vs 33.0% (RR 1.29; P=.054).

Criticisms

Open-label design, though outcomes were assessed by blinded assessors with independent audio review — residual performance bias possible
Conducted exclusively in Chinese population (48 centers); generalizability to other races/ethnicities is uncertain
Symptomatic ICH rate of 2.8% vs 0% is concerning; 2 of 21 patients with mismatch inconsistency (CT hypodensity exceeding CTP core) developed sICH, suggesting careful NCCT review is critical
Functional independence (mRS 0–2) did not reach significance in unadjusted analysis (P=.07), though adjusted analysis was significant (P=.03)
23.3% of patients had stenosis without occlusion rather than true MeVO/distal occlusion — mixed pathophysiology
Very small ischemic cores (median 0–1 mL) indicate a highly selected favorable population; benefit may not extend to those with larger cores
Planned interim analysis was not conducted due to rapid enrollment — no α was spent but deviates from original statistical plan
Rescue thrombectomy was permitted (6 tenecteplase, 1 control) — though post hoc analysis adjusting for this showed consistent results
CTP software (CTPdoc, Shukun Technology) is not widely validated outside China; posterior circulation CTP thresholds are not well established
90-day mortality was numerically higher with tenecteplase (5.0% vs 3.2%), and the trial was not powered to assess mortality as a safety endpoint
Dominant M2 occlusions were not excluded despite emerging thrombectomy evidence for this subgroup (ESCAPE-MeVO, DISTAL)

Funding

Beijing Hospitals Authority Clinical Medicine Development of special funding support (ZLRK202514) and CSPC Recomgen Pharmaceutical (Guangzhou) Co LTD (provided study drug). Neither funder had a role in design, conduct, analysis, interpretation, manuscript preparation, or submission decision.

Based on: OPTION (JAMA, 2026)