Intra-arterial recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) thrombolysis for acute medium vessel occlusion (MeVO-TNK): Study rationale and design

Technical Summary: The MeVO-TNK Trial

Problem Statement
The optimal reperfusion strategy for acute ischemic stroke (AIS) caused by medium vessel occlusion (MeVO) remains uncertain. While MeVO accounts for approximately 25–40% of AIS cases, current standard medical management often fails to achieve functional independence in one-third of patients. Recent randomized trials evaluating endovascular therapy (EVT) for MeVO have yielded mixed results, with several studies failing to demonstrate a clear clinical benefit over best medical management and raising concerns regarding procedure-related complications. Consequently, there is a need for alternative reperfusion strategies that balance efficacy with safety. Intra-arterial thrombolysis (IAT) offers a biologically plausible alternative by avoiding mechanical manipulation of distal vessels, yet prospective evidence supporting IAT specifically for MeVO is lacking. Furthermore, no prospective study has evaluated intra-arterial tenecteplase (IA-TNK) as a stand-alone treatment for this population, despite tenecteplase's favorable pharmacological profile (higher fibrin specificity, increased resistance to plasminogen activator inhibitor-1, and longer half-life compared to alteplase).

Methodology
The MeVO-TNK trial is a multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE), exploratory phase II study designed to evaluate IA-TNK.

• Study Design: Conducted across 14 comprehensive stroke centers in China, the study randomizes participants in a 1:1 ratio to either IA-TNK plus standard medical therapy (SMT) or SMT alone.
• Participants: The trial enrolls 60 adults with imaging-confirmed acute isolated MeVO within 24 hours of symptom onset. For patients presenting beyond 6 hours, advanced imaging must demonstrate salvageable penumbral tissue. Key exclusion criteria include pre-stroke disability, intracranial hemorrhage, and planned mechanical thrombectomy.
• Intervention:
  • IA-TNK Group: Patients receive a microcatheter-delivered bolus of tenecteplase (0.0625 mg/kg, max 6.25 mg) at the proximal end of the occlusion. Reperfusion is assessed 5 minutes post-infusion via angiography using the expanded Thrombolysis in Cerebral Infarction (eTICI) score. A second identical bolus is administered only if reperfusion is <eTICI 2b50 and no hemorrhage is observed.
  • Control Group: Patients receive SMT alone. No intra-arterial thrombolytics or mechanical thrombectomy are permitted after randomization.
• Outcomes:
  • Primary Efficacy: Final infarct volume (FIV) measured at 72 ± 24 hours post-randomization (preferentially via MRI-DWI), adjusted for baseline infarct core volume.
  • Secondary Efficacy: Modified Rankin Scale (mRS) scores (0–1, 0–2, 0–3) at 90 days, mRS shift analysis, early neurological deterioration, and NIHSS scores.
  • Primary Safety: Symptomatic intracranial hemorrhage (sICH) within 24 hours.
• Analysis: The primary analysis follows an intention-to-treat (ITT) approach using a generalized linear model (GLM) with a Gamma distribution and log link. The study is powered for feasibility and preliminary estimation rather than definitive hypothesis testing.

Key Contributions
This paper outlines the rationale and design of the first prospective, randomized trial specifically evaluating stand-alone IA-TNK for acute MeVO. Its primary contributions include:

1. Addressing an Evidence Gap: It targets the lack of prospective data regarding IAT and IA-TNK specifically for MeVO, a population where EVT benefits remain controversial.
2. Stepwise Dosing Strategy: The study explores a conditional, stepwise dosing protocol (initial bolus followed by a conditional second bolus based on angiographic response) to optimize the balance between reperfusion efficacy and hemorrhagic risk.
3. Refined Patient Selection: By utilizing advanced imaging to identify salvageable tissue for late-presenters (>6 hours), the trial aims to enrich the population with patients most likely to benefit from reperfusion.
4. Rigorous Blinding: Despite the open-label treatment allocation, the study employs blinded outcome assessment by independent core laboratories for imaging and functional outcomes, mitigating bias in endpoint evaluation.

Results
As a study protocol and rationale paper, the MeVO-TNK trial has not yet reported clinical results. The manuscript details the study design, eligibility criteria, and statistical analysis plan. Recruitment began in November 2024 and was completed in July 2025, but the paper does not contain efficacy or safety data from the enrolled participants.

Significance and Claims
The authors position the MeVO-TNK trial as a critical step toward resolving the uncertainty surrounding MeVO management. The study claims to provide preliminary evidence regarding the biological efficacy, reperfusion potential, and safety of stand-alone IA-TNK.

• Future Guidance: The authors state that the findings will help address the current evidence gap and inform the design of future confirmatory, definitive trials.
• Clinical Impact: A positive result could support IA-TNK as a novel treatment option for MeVO, particularly for distal or tortuous occlusions where mechanical thrombectomy is challenging. Conversely, a negative result would provide critical evidence to guide future investigations toward alternative strategies or refined patient selection.
• Modesty: The authors explicitly acknowledge the study's limitations, noting that as an exploratory phase II trial with a small sample size (n=60), it is not powered to detect modest treatment effects or support definitive subgroup analyses. They emphasize that the primary endpoint (FIV) is a surrogate outcome and that the open-label nature of the treatment may introduce variability. The study is framed as hypothesis-generating rather than conclusive.