NCT03785678: TIMELESS

Tenecteplase in Stroke Patients Between 4.5 and 24 Hours

Completed Phase 3 Results posted Last updated 22 May 2024

What this trial tests

Phase 3 trial testing Tenecteplase in THROMBOLYSIS in 458 participants. Completed in 28 February 2023.

Timeline

2 March 2019

Primary endpoint
28 February 2023

28 February 2023

Quick facts

Lead sponsor	Genentech, Inc.
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	458
Start date	2 March 2019
Primary completion	28 February 2023
Estimated completion	28 February 2023
Sites	97 locations across Canada, United States

Drugs / interventions tested

• Tenecteplase (TENECTEPLASE) — full drug profile →
• Placebo

Conditions studied

• THROMBOLYSIS — all drugs for THROMBOLYSIS →

Sponsor

Genentech, Inc. — full company profile →

Who can join

18 and older, any sex, with THROMBOLYSIS. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Ordinal Modified Rankin Scale (mRS) Score at Day 90 Primary · Day 90

The the modified Rankin score (mRS) is a 6-point scale commonly used to assess disability due to stroke, with higher values indicating worse outcomes. 0 = No symptoms 1. = No significant disability 2. = Slight disability 3. = Moderate disability 4. = Moderately severe disability 5. = Severe disability 6. = Death

0

Group	Value	95% CI
Tenecteplase	35
Placebo	31

1

Group	Value	95% CI
Tenecteplase	38
Placebo	30

2

Group	Value	95% CI
Tenecteplase	31
Placebo	36

3

Group	Value	95% CI
Tenecteplase	34
Placebo	41

4

Group	Value	95% CI
Tenecteplase	29
Placebo	34

5

Group	Value	95% CI
Tenecteplase	15
Placebo	13

6

Group	Value	95% CI
Tenecteplase	44
Placebo	44

Proportion of Patients With Functional Independence at Day 90 Secondary · Day 90

Functional independence, was defined as an mRS of 0-2 (no symptoms to mild symptoms), at Day 90.

mRS ≤ 2 at Day 90

Group	Value	95% CI
Tenecteplase	46.0
Placebo	42.4

mRS > 2 at Day 90

Group	Value	95% CI
Tenecteplase	54.0
Placebo	57.6

Proportion of Patients With Recanalization at 24 Hours Post-randomization Secondary · Day 2

This endpoint measured complete or partial recanalization (restored blood flow) on CT angiography (CTA)/magnetic resonance angiography (MRA) post-randomization, defined as complete or partial recanalization on CT angiography (CTA)/magnetic resonance angiography (MRA).

Complete recanalization

Group	Value	95% CI
Tenecteplase	76.7
Placebo	63.9

None or partial recanalization

Group	Value	95% CI
Tenecteplase	23.3
Placebo	36.1

Proportion of Patients With Reperfusion at 24 Hours Post-randomization Secondary · Day 2

This endpoint was defined by the proportion of participants with reperfusion (the restoration of blood flow to an organ or tissue after having been blocked) at 24 hours post-randomization, defined as \> 90% reduction in Tmax \> 6s lesion volume.

> 90% reduction in Tmax > 6s lesion volume

Group	Value	95% CI
Tenecteplase	56.9
Placebo	57.7

≤ 90% reduction

Group	Value	95% CI
Tenecteplase	43.1
Placebo	42.3

Proportion of Patients With Angiographic Reperfusion at Completion of Angiographic Procedure Secondary · Day 1

Angiographic reperfusion was evaluated using the modified Thrombolysis in Cerebral Infarction (TICI) Scale: 0: No perfusion or anterograde flow beyond site of occlusion. 1. Contrast passes the area of occlusion but fails to opacify the entire cerebral bed distal to the obstruction during angiographic run. 2. Partial perfusion wherein the contrast passes the occlusion and opacifies the distal arterial bed but rate of entry or clearance from the bed is slower than non-involved territories 2A: \< 50% of territory visualized 2B: ≥ 50% of territory is visualized 2C: Near complete perfusion except

Achieving TICI 2b or TICI 3

Group	Value	95% CI
Tenecteplase	89.1
Placebo	85.4

Achieving TICI < 2b

Group	Value	95% CI
Tenecteplase	10.9
Placebo	14.6

Median NIHSS Score at Day 90 Secondary · Day 90

The National Institutes of Health Stroke Score (NIHSS) is a 15-item scale that measures neurological deficit in acute stroke patients. Each item is ranked using a 3-, 4-, or 5-point scale, including allowances for items that cannot be scored due to the patient's condition, with higher scores indicating more severe deficit. Total scores range from 0-42, with higher scores indicating more severe deficits.

Group	Value	95% CI
Tenecteplase	1.0	0 – 31
Placebo	1.0	0 – 26

Proportion of Patients With a Barthel Index (BI) Score ≥ 95 at Day 90 Secondary · Day 90

The Barthel Index (BI) is a 10-item ordinal scale used to measure performance in activities of daily living (ADL) and mobility. The BI scoring range is from 0-100, with lower scores representing greater dependency.

BI score ≥ 95 at Day 90

Group	Value	95% CI
Tenecteplase	60.5
Placebo	58.4

BI score < 95 at Day 90

Group	Value	95% CI
Tenecteplase	39.5
Placebo	41.6

Proportion of Patients With Good Recovery Based on the Glasgow Outcome Scale (GOS) at Day 90 Secondary · Day 90

The Glasgow Outcome Scale (GOS) is a scale used to assess recovery of participants with brain damage. The scale has 5 categories: 1. = Death 2. = Persistent vegetative state 3. = Severe disability 4. = Moderate disability 5. = Good recovery The GOS was re-scaled from observed data. For this measure, 1 = good recovery and 5 = death.

Good recovery GOS score (=1)

Group	Value	95% CI
Tenecteplase	36.5
Placebo	30.8

GOS score > 1

Group	Value	95% CI
Tenecteplase	63.5
Placebo	69.2

Incidence of Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours Secondary · Within 36 hours (Day 2) of treatment

Group	Value	95% CI
Tenecteplase	3.2
Placebo	2.3

Mortality Rate up to Day 30 and Day 90 Secondary · Day 30 and Day 90

Death within 30 days

Group	Value	95% CI
Tenecteplase	14.7
Placebo	15.0

Death within 90 days

Group	Value	95% CI
Tenecteplase	19.7
Placebo	18.2

Proportion of Patients With Parenchymal Hematoma Type 2 (PH2) at the 72-96 Hour Visit Secondary · Day 3

Group	Value	95% CI
Tenecteplase	3.7
Placebo	2.8

Adverse events — posted to ClinicalTrials.gov

Time frame: From treatment visit to Day 90 follow-up. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Tenecteplase

Serious: 91/218 (42%)

Deaths: 44/228

Placebo

Serious: 102/214 (48%)

Deaths: 44/230

Serious adverse events (153 terms)

Reaction	System	Tenecteplase	Placebo
Stroke in evolution	Nervous system disorders	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Hypotension	Vascular disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Brain oedema	Nervous system disorders	—	—
Cerebral artery occlusion	Nervous system disorders	—	—
Cerebrovascular accident	Nervous system disorders	—	—
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Sepsis	Infections and infestations	—	—
Subarachnoid haemorrhage	Nervous system disorders	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—
Pneumonia	Infections and infestations	—	—
Urinary tract infection	Infections and infestations	—	—
Haemorrhage intracranial	Nervous system disorders	—	—
Intraventricular haemorrhage	Nervous system disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Pneumonia aspiration	Infections and infestations	—	—
Cerebral haemorrhage	Nervous system disorders	—	—
Bradycardia	Cardiac disorders	—	—
Cardiac arrest	Cardiac disorders	—	—
Cardio-respiratory arrest	Cardiac disorders	—	—
Dysphagia	Gastrointestinal disorders	—	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—
Death	General disorders	—	—

Other adverse events (16 terms — click to expand)

Reaction	System	Tenecteplase	Placebo
Urinary tract infection	Infections and infestations	—	—
Haemorrhagic transformation stroke	Nervous system disorders	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—
Cerebral haemorrhage	Nervous system disorders	—	—
Headache	Nervous system disorders	—	—
Haemorrhagic infarction	Vascular disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Subarachnoid haemorrhage	Nervous system disorders	—	—
Hypotension	Vascular disorders	—	—
Pyrexia	General disorders	—	—
Haemorrhage intracranial	Nervous system disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Dysphagia	Gastrointestinal disorders	—	—
Haematoma	Vascular disorders	—	—
Pneumonia	Infections and infestations	—	—

Most-reported serious reactions: Stroke in evolution, Respiratory failure, Hypotension, Anaemia, Brain oedema, Cerebral artery occlusion, Cerebrovascular accident, Acute respiratory failure.

Data from ClinicalTrials.gov NCT03785678 adverse events section.

Sponsor's own description

This study will evaluate the efficacy and safety of tenecteplase compared with placebo in participants with acute ischemic stroke (AIS).

All participants will receive standard-of-care therapy according to AmericanHeart Association/American Stroke Association clinical guidelines (2018). To determine eligibility for randomization, all participants will undergo multimodal CT or MRI at baseline. Only participants with a vessel occlusion (ICA or MCA M1/M2) and penumbral tissue will be randomized. The primary analysis is to compare the efficacy of tenecteplase versus placebo in all participants at Day 90.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke.
   Berge E, Whiteley W, Audebert H, De Marchis GM, et al · · 2021 · cited 816× · PMID 33817340 · DOI 10.1177/2396987321989865
2. Effect of Long-term Continuous Cardiac Monitoring vs Usual Care on Detection of Atrial Fibrillation in Patients With Stroke Attributed to Large- or Small-Vessel Disease: The STROKE-AF Randomized Clinical Trial.
   Bernstein RA, Kamel H, Granger CB, Piccini JP, et al · · 2021 · cited 153× · PMID 34061145 · DOI 10.1001/jama.2021.6470
3. Tenecteplase Thrombolysis for Acute Ischemic Stroke.
   Warach SJ, Dula AN, Milling TJ. · · 2020 · cited 150× · PMID 33045929 · DOI 10.1161/strokeaha.120.029749
4. European Stroke Organisation (ESO) expedited recommendation on tenecteplase for acute ischaemic stroke.
   Alamowitch S, Turc G, Palaiodimou L, Bivard A, et al · · 2023 · cited 141× · PMID 37021186 · DOI 10.1177/23969873221150022
5. Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection.
   Albers GW, Jumaa M, Purdon B, Zaidi SF, et al · · 2024 · cited 105× · PMID 38329148 · DOI 10.1056/nejmoa2310392
6. Acute Stroke Management: Overview and Recent Updates.
   Hollist M, Morgan L, Cabatbat R, Au K, et al · · 2021 · cited 79× · PMID 34221544 · DOI 10.14336/ad.2021.0311
7. European Stroke Organisation - European Society for Minimally Invasive Neurological Therapy expedited recommendation on indication for intravenous thrombolysis before mechanical thrombectomy in patients with acute ischaemic stroke and anterior circulation large vessel occlusion.
   Turc G, Tsivgoulis G, Audebert HJ, Boogaarts H, et al · · 2022 · cited 75× · PMID 35300256 · DOI 10.1177/23969873221076968
8. Access to Mechanical Thrombectomy for Ischemic Stroke in the United States.
   Kamel H, Parikh NS, Chatterjee A, Kim LK, et al · · 2021 · cited 66× · PMID 33980045 · DOI 10.1161/strokeaha.120.033485