TNK vs tPA — The ORIGINAL Trial

Written by Carlton Watson, MD, MSc
REBEL Crit, REBEL EM
Medical Category: Neurology
Acute Ischemic Stroke, Alteplase, Spectrum Bias, stroke, Tenecteplase, thrombolysis, TNK, tPA

May 5, 2025

📌 REBEL Recap

- 💊 TNK was non-inferior to tPA for excellent outcomes (mRS 0–1 at 90 days)
- 🎯 High proportion of mild strokes may introduce spectrum bias, making non-inferiority easier to demonstrate
- 🕒 Slightly more TNK patients treated within 3 hours — could affect results
- 📉 No difference in mortality, bleeding, or serious adverse events
- ⚖️ Findings support TNK as an alternative to tPA

📝 Introduction

The American Heart Association and the European Stroke Organization have updated their guidelines to recommend tenecteplase (TNK) as an alternative to alteplase (tPA) in patients eligible for thrombolysis.^1,2 TNK, a bioengineered variant of tPA, has some advantages, including its single-dose administration, fibrin specificity, and longer half-life. Several studies have demonstrated the safety and efficacy of TNK as an alternative to tPA.^3–10

The ORIGINAL trial evaluated the noninferiority of TNK compared to tPA in Chinese patients with acute ischemic stroke (AIS). By addressing a geographic evidence gap, the study aimed to provide insights into the applicability of TNK and further validate its use within this population.11 This review explores the trial’s findings, its implications for stroke management, and the potential role of tenecteplase in global and regional stroke care.

COVERED ON REBEL EM:

- The AcT Trial
- TASTE-A and NOR-TEST 2
- Tenecteplase for Thrombolysis of AIS
- EXTEND-IA TNK
- EXTEND-IA – TNK Part II

🧾 Paper

Meng X, Li S, Dai H, et al. Tenecteplase vs Alteplase for Patients With Acute Ischemic Stroke: The ORIGINAL Randomized Clinical Trial. JAMA. 2024;332(17):1437-1445. PMID: 39264623

⚙️ What They Did

CLINICAL QUESTION

In adults with acute ischemic stroke eligible for intravenous thrombolysis within 4.5 hours of symptom onset, is TNK as effective as tPA in achieving excellent functional outcomes at 90 days?

STUDY DESIGN

Phase 3, multicenter, randomized, open-label, blinded-endpoint non-inferiority trial at 55 stroke centers in China
Patients with AIS were randomized 1:1 to receive TNK or tPA
Stratified randomization by:
- Baseline NIHSS: <6, 6–15, >15
- Age: ≤80, >80 years
Baseline non-contrast CT used to exclude intracranial hemorrhage
Primary outcome (modified Rankin Scale 0–1 at day 90) assessed by blinded, trained neurologists
Secondary outcomes included:
- Major neurologic improvement at 24h
- mRS 0–2, Barthel Index ≥95
- Change in NIHSS and ordinal mRS distribution at day 90
Follow-up assessments at 2h, 24h, 1 week, 1 month, and 3 months
Safety monitoring included:
- sICH (ECASS III definition)
- 90-day all-cause mortality
- Systemic bleeding and angioedema
Analyses included multiple imputation, per-protocol, and subgroup approaches
Non-inferiority margin: RR 0.937, preserving ≥50% of tPA’s known effect

POPULATION

Inclusion Criteria:

- Age ≥18 years
- Diagnosis of acute ischemic stroke (AIS)
- National Institutes of Health Stroke Scale (NIHSS) score of 1 to 25
- Presence of a measurable neurologic deficit
- Symptomatic for at least 30 minutes without significant improvement
- Able to receive intravenous thrombolysis within 4.5 hours of symptom onset
- If NIHSS score <4, must have had a motor function score ≥1 in arm or leg
- Patients planned for endovascular thrombectomy were also eligible

Exclusion Criteria:

Imaging or Clinical Indicators of High Risk
- Intracranial hemorrhage on CT
- Symptoms suggestive of subarachnoid hemorrhage (even with normal CT)
- Multilobar infarction on CT (hypodensity >1/3 of cerebral hemisphere)
Bleeding Diathesis or Risk
- Suspected intracranial or subarachnoid hemorrhage due to aneurysm
- Known CNS neoplasm, aneurysm, or recent intracranial/spinal surgery
- Neoplasm with increased hemorrhage risk
- Known bleeding disorder or history of significant bleeding within 6 months
- Recent (past 48 hrs) heparin use with elevated aPTT
- Warfarin use with INR >1.7 or PT >15
- DOAC use (e.g., apixaban, dabigatran, rivaroxaban) with elevated aPTT/PT
- Platelet count <100,000/mm³
- Traumatic CPR, obstetrical delivery, or non-compressible vessel puncture (e.g., subclavian/jugular) within 10 days
- Active GI ulcers (past 3 months), esophageal varices, aneurysms, or AVMs
- Any disorder significantly increasing bleeding risk
Medication Conflicts
- Use or planned use of any thrombolytic other than study drug
- Use of antiplatelets, oral anticoagulants, or IV heparin within 24 hours post-treatment
- Exception: low-dose subcutaneous heparin (<10,000 IU/day) allowed if aPTT ≤ 2x baseline
- IV heparin only allowed ≥24 hours after study drug and repeat CT excludes ICH
Active or Recent Conditions
- Bacterial endocarditis, pericarditis, or acute pancreatitis
- Major trauma or surgery within the past 3 months
- Severe uncontrolled hypertension (SBP >185 mmHg or DBP >110 mmHg)
- Hypoglycemia (blood glucose <50 mg/dL)
- Seizure at stroke onset
- COVID-19 diagnosis within the past 3 months
Other Conditions
- Pregnant
- Known allergy to tPA, TNK, gentamicin, or any excipient
- Participation in another clinical trial within the past 29 days
- Any condition that poses risk to safety or may interfere with study completion

INTERVENTION & COMPARATOR

Intervention:

TNK, administered as a single intravenous bolus at 0.25 mg/kg, with a maximum dose of 25 mg.

Comparator:

tPA, administered as an intravenous dose of 0.9 mg/kg, with a maximum dose of 90 mg.
10% of the dose was given as an initial bolus
The remaining 90% was infused over 1 hour

OUTCOMES

Primary Outcome:

- Proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 at day 90
- Definition: Excellent functional outcome — no symptoms (0) or no significant disability despite symptoms

Secondary Outcomes:

- Major neurologic improvement at 24 hours
- Defined as NIHSS score of 0 or at least a 4-point improvement from baseline
- mRS score of 0–2 at day 90
- Change in NIHSS score from baseline to day 90
- Distribution of mRS scores at day 90 (ordinal analysis)
- Barthel Index score ≥95 at day 90

Efficacy Outcomes:

- mRS ≤1 and ≤2 at day 30
- Barthel Index ≥95 at day 30
- Barthel Index ≥85 at day 90
- Glasgow Outcome Scale score of 1 at day 90
- NIHSS:
  - NIHSS at 2h, 24h, day 8, and day 30
  - ≥8-point improvement or NIHSS ≤1 at day 30
  - ≥4-point improvement or NIHSS ≤1 at day 8

Safety Outcomes:

- Symptomatic intracerebral hemorrhage (sICH) up to 36 hours post-treatment, defined by:
  - ECASS III (primary safety outcome)
- SITS-MOST
- ECASS II
- All-cause mortality within 90 days
- mRS score of 5 or 6 at day 90 (severe disability or death)
- Intracranial hemorrhage on imaging
  - Including subtypes: HI1, HI2, PH1, PH2
- Systemic bleeding events: Gastrointestinal, mucocutaneous, urological, etc.
  - Angioedema events (e.g., eyelid, lip, tongue swelling)
- Serious adverse events (SAEs) and adverse events leading to drug discontinuation

📈 Results

Outcomes

Demographics

Outcomes

Demographics

💥 Critical Results

- TNK group: 532 out of 732 patients (72.7%) achieved mRS 0–1
- tPA group: 515 out of 733 patients (70.3%) achieved mRS 0–1
- Risk Ratio (RR):1.03, (95% CI: 0.97 to 1.09)
- Risk Difference: +2.12% in favor of TNK, (95% CI: –2.17% to +6.40%)
- Non-inferiority margin (RR): 0.937, The lower bound of the 95% CI (0.97) did not cross the margin → non-inferiority confirmed

💪 Strengths

- Randomized controlled trial design ensures a high level of internal validity for comparing treatments.
- Clearly defined non-inferiority margin (RR 0.937) supports the credibility of the study’s aim.
- Blinded mRS outcome assessment reduces bias despite the open-label nature of the trial.
- Central adjudication of sICH enhances reliability and uniformity in safety outcome classification.
- Detailed protocol and statistical plan strengthen the validity through predefined sensitivity and subgroup analyses.
- Large sample size (N=1489) across 55 sites provides sufficient power and improves generalizability.
- Broad, pragmatic inclusion criteria allow application of findings to a real-world AIS population.
- Baseline characteristics well-matched between groups, reducing risk of confounding.
- Clinically meaningful primary outcome (mRS 0–1 at 90 days) aligns with functional recovery goals in stroke care.
- Comprehensive secondary outcomes provide additional insight into neurologic recovery and safety.
- Adherence to CONSORT guidelines ensures transparent and standardized reporting.
- Justified non-inferiority margin preserves a clinically meaningful portion of tPA’s known benefit.
- Use of relative effect (RR) for primary analysis is appropriate for non-inferiority trial design.
- Both ITT and per-protocol analyses performed to confirm the robustness of non-inferiority conclusion.
- High trial completion rate (90.4%) limits attrition bias and supports reliability of outcomes.

⚠️ Limitations

- Open-label design introduces potential performance bias, as treating clinicians were not blinded to therapy.
- Industry funding and sponsor involvement introduce publication bias and funding bias.
- No formal superiority testing limits the ability to detect true differences beyond non-inferiority.
- Single-country (China) setting reduces generalizability to non-Chinese populations and international practice settings.
- Underrepresentation of women (~30%) limits applicability to the broader stroke population.
- Low median NIHSS score (6) may reduce relevance to patients with moderate or severe strokes.
- Low CTA/MRA rate (<25%) and thrombectomy rate (<10%) may not reflect modern stroke workflows, particularly in LVO cases.
- Change in non-inferiority margin during planning may introduce perceptions of bias despite transparency.
- No adjudication of stroke mimics may dilute the treatment effect, especially in mild stroke presentations.
- Dichotomizing mRS at 0–1 may overlook meaningful improvements across the broader disability spectrum.
- Use of imputation (e.g., multiple imputation, LOCF) introduces assumptions that could bias results.
- Short safety follow-up for sICH (36 hours) may miss later-occurring adverse events.
- Extensive exclusion criteria may restrict generalizability and introduce selection bias.
- Unclear if mRS was assessed in person or remotely, which may affect the reliability of functional outcome assessment.

🗣️ Discussion

SPECTRUM BIAS — LOW NIHSS

Spectrum bias occurs when outcomes are influenced by enrolling patients at only one end of the disease severity spectrum. Approximately 40% of participants in the ORIGINAL trial had a baseline NIHSS <6 before treatment, indicating mild strokes. While these patients were evenly distributed between the treatment arms, the inclusion of many patients with mild symptoms makes it easier for investigators to prove non-inferiority of the intervention.

Patients with mild deficits are more likely to achieve favorable outcomes due to chance alone, regardless of treatment. In the context of a non-inferiority trial, enrolling patients with mild strokes can inflate the overall rate of good outcomes in both groups, making it easier to demonstrate non-inferiority—even if there are small, real differences in treatment effect. In other words, the true effect may be drowned out by spontaneous recovery.

SUBJECTIVE FUNCTIONAL ASSESSMENTS

The trial used well-established outcome measures—such as the modified Rankin Scale (mRS), Barthel Index, and Glasgow Outcome Scale—that are standard in stroke research and allow comparison with other studies on TNK. However, these tools are inherently subjective, which introduces a key limitation, particularly in non-inferiority trials.

Unlike superiority trials, the aim here isn’t to show that TNK is better—just that it’s not significantly worse. When outcome differences are subtle, assessors may (consciously or not) assign similar scores across groups. This subjectivity can obscure small but clinically relevant differences, potentially biasing the results toward non-inferiority.

- Modified Rankin Scale (Link on MDCalc):
  Although it’s the gold standard for measuring functional independence post-stroke, it can be influenced by how well-trained the assessor is, how much information they have, and whether the interview is done in person or over the phone. Even with certification, inter-rater variability remains an issue, particularly when differentiating between scores like 1 vs 2 or 2 vs 3.
- Barthel Index (Link to MDCalc):
  This tool focuses on basic activities of daily living (e.g., feeding, bathing, walking), which is helpful, but may miss nuances in cognitive or communication deficits. It’s also patient- or caregiver-reported, introducing recall bias.
- Glasgow Outcome Scale (GOS):
  Originally developed for traumatic brain injury, the GOS is a broad-brush scale and may be too coarse to detect subtle differences in stroke recovery, especially in mild cases.

MORE TNK PATIENTS TREATED WITHIN 3 HOURS

Another subtle but important finding was that 54.9% of patients in the TNK group received treatment within 3 hours of symptom onset, compared to 51.2% in the tPA group — a 3.7% difference. This imbalance, although not emphasized in the trial, favors TNK and could have influenced the primary outcome (mRS 0–1 at 90 days: 72.7% vs 70.3%).

It’s unclear whether this timing imbalance was due to chance or logistical factors (e.g., TNK’s bolus-only administration being faster to prepare and deliver). Given that the study was a non-inferiority trial, even minor baseline differences can affect results — especially when the absolute difference in outcomes is just over 2%.

📊 State of The Evidence

Study	Design / N	Primary Outcome Result	Outcome
ATTEST (2015) Alteplase–Tenecteplase Trial Evaluation for Stroke Thrombolysis	Phase II, single-center PROBE, N=104	% penumbra salvaged (24–48h): 68% (TNK) vs 68% (tPA); no difference	Negative
NOR-TEST (2017) Norwegian Tenecteplase Stroke Trial (predominantly mild strokes)	Phase III, open-label, N≈1100	mRS 0–1 at 90d: 64% (TNK) vs 63% (tPA); OR 1.08, p=0.52	Negative
EXTEND-IA TNK (2018) Tenecteplase vs Alteplase Before Endovascular Therapy	Phase II, bridging thrombolysis, N=202	Early reperfusion: 22% (TNK) vs 10% (tPA); p=0.04	Positive
TASTE-A (2022) Tenecteplase vs Alteplase in Ambulance (MSU)	Phase II, prehospital setting, N=104	Smaller perfusion lesion: 12mL (TNK) vs 35mL (tPA); p=0.003	Positive
NOR-TEST 2 Part A (2022) TNK (0.4 mg/kg) vs Alteplase in moderate/severe stroke	Phase III, open-label NI, N=208	mRS 0–1: 32% (TNK) vs 51% (tPA); OR 0.45, p=0.0064	Negative
TRACE (2022) Tenecteplase Reperfusion Therapy in AIS	Phase II, PROBE, China, N=236	NIHSS improvement at 14d: no significant difference	Negative
AcT (2022) Alteplase Compared to Tenecteplase in Real-World Practice	Phase III, pragmatic NI, Canada, N=1600	mRS 0–2 at 90d: ~60% (TNK) vs ~58% (tPA); NI met	Positive
TRACE-2 (2023) Tenecteplase vs Alteplase (Early Window, Non-EVT)	Phase III, NI, China, N=1417	mRS 0–1 at 90d: 62% (TNK) vs 58% (tPA); NI met	Positive
ORIGINAL (2024) Tenecteplase vs Alteplase for AIS ≤4.5h	Phase III, NI, China, N=1489	mRS 0–1 at 90d: 72.7% (TNK) vs 70.3% (tPA); NI met	Positive
TASTE (2024) Perfusion Imaging Selection for Thrombolysis	Phase III, NI, N=680	mRS 0–1 at 90d: 54% (TNK) vs 50% (tPA); NI met	Positive
ATTEST-2 (2024) Tenecteplase vs Alteplase Within 4.5h of Stroke	Phase III, NI, N=1200	mRS 0–2 at 90d: 65% (TNK) vs 63% (tPA); NI met	Positive
Late Window TNK (2024) Tenecteplase vs Standard Care in 4.5–24h Window (No tPA)	Phase III, NI, N=516	mRS 0–1 at 90d: 33.0% (TNK) vs 24.2% (Std Care); p=0.03	Positive

📘 Author's Conclusion

“In patients with AIS eligible for intravenous thrombolysis within 4.5 hours after stroke onset, tenecteplase was non-inferior to alteplase with respect to excellent functional outcome (mRS score of 0 or 1) at 90 days and had a similar safety profile. Findings from this study support tenecteplase as a suitable alternative to alteplase in this setting.”

💬 Our Conclusion

The ORIGINAL Trial supports TNK as a safe, effective alternative to tPA for AIS, reinforcing findings from other large trials. Its single-bolus administration offers clear advantages, especially in resource-limited settings. These findings align with current guidelines endorsing TNK. However, the inclusion of many patients with mild strokes, a slightly higher proportion of early treatment in the TNK group, and the use of subjective outcome measures like the mRS may bias results toward non-inferiority.

🚨 Clinical Bottom Line

TNK is a safe, effective, and logistically simpler alternative to tPA for the treatment of acute ischemic stroke within 4.5 hours.

📚 References

Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association [published correction appears in Stroke. 2019 Dec;50(12):e440-e441. PMID: 31662037
Alamowitch S, Turc G, Palaiodimou L, et al. European Stroke Organisation (ESO) expedited recommendation on tenecteplase for acute ischaemic stroke. Eur Stroke J. 2023;8(1):8-54. PMID: 37021186
Memon BK et. Intravenous tenecteplase compared with alteplase for acute ischemic stroke in Canada (AcT): a pragmatic, multicenter, open-label, registry-linked, randomized, controlled, non-inferiority trial. Lancet. 2022. PMID: 35779553
Bala F, Singh N, Buck B, et al. Safety and Efficacy of Tenecteplase Compared With Alteplase in Patients With Large Vessel Occlusion Stroke: A Prespecified Secondary Analysis of the ACT Randomized Clinical Trial. JAMA Neurol. 2023;80(8):824–832. PMID: 37428494
Bivard A et al. Comparison of Tenecteplase with Alteplase for the Early Treatment of Ischaemic Stroke in the Melbourne Mobile Stroke Unit (TASTE-A): A Phase 2, Randomised, Open-Label Trial. Lancet Neurol 2022. PMID: 35525251
Kvistad CE et al. Tenecteplase Versus Alteplase for the Management of Acute Ischaemic Stroke in Norway (NOR-TEST 2, Part A): A Phase 3, Randomised, Open-Label, Blinded Endpoint, Non-Inferiority Trial. Lancet Neurol 2022. PMID: 35525250
Oliveira M et al. Tenecteplase for Thrombolysis in Stroke Patients: Systematic Review With Meta-Analysis. AJEM 2021. PMID: 33440328
Campbell BCV et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. NEJM; 378(17): 1573-1582. PMID: 29694815
Campbell BCV et al. Effect of intravenous tenecteplase dose on cerebral repercussion before thrombectomy in patient with large vessel occlusion ischemic stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial. JAMA 2020. PMID: 32078683
Warach SJ, Ranta A, Kim J, et al. Symptomatic Intracranial Hemorrhage With Tenecteplase vs Alteplase in Patients With Acute Ischemic Stroke: The Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischemic Stroke (CERTAIN) Collaboration. JAMA Neurol. 2023;80(7):732–738. PMID: 37252708
Meng X, Li S, Dai H, et al. Tenecteplase vs Alteplase for Patients With Acute Ischemic Stroke: The ORIGINAL Randomized Clinical Trial. JAMA. 2024;332(17):1437-1445. PMID: 39264623

👤 Guest Contributor

Carlton Watson

MD, MSc

PGY-3 Emergency Medicine Resident Nuvance Health, Poughkeepsie, NY

Meet The Team

🔎 Your Deep-Dive Starts Here

Cite this article as: Carlton Watson, MD, MSc, "TNK vs tPA — The ORIGINAL Trial", REBEL EM blog, May 5, 2025. Available at: https://rebelem.com/tnk-vs-tpa-the-original-trial/.

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