Tenecteplase versus Alteplase for Management of Acute Ischaemic Stroke (NOR-TEST): a Phase 3, Randomised, Open-label, Blinded Endpoint Trial

Design

Phase 3, randomized, open-label, blinded endpoint trial

N= 1,100

Objective

To investigate the safety and efficacy of tenecteplase versus alteplase in patients with acute stroke who were eligible for intravenous thrombolysis

Study Groups

Tenecteplase (n= 549)

Alteplase (n= 551)

Inclusion Criteria

Patients admitted within 4-5 hours of symptom onset, were 18+ years of age, independently living pre-stroke and were eligible for intravenous (IV) thrombolysis

Exclusion Criteria

Patients with a contraindication for the treatment therapies

Methods

Patients were randomized (1:1) to receive either IV tenecteplase 0.4 mg/kg up to a max dose of 40 mg or alteplase 0.9 mg/kg up to a max of 90 mg. Neurological defects were measured at 2 hours, 24-48 hours, and 7 days after treatment (or discharge). The Modified Rankin Scale was assessed at day 7 or discharge and approximately 3 months afterward via telephone.

Duration

September 1, 2012 to September 30, 2016

Outcome Measures

Primary outcome: Modified Rankin Scale (mRS) Score 0-1 at 3 months

Secondary outcome: Any intracranial hemorrhage (ICH) at 24-48 hours (any hemorrhagic transformations or parenchymal hematoma according to European Cooperative Acute Stroke Study [ECASS] I criteria), symptomatic ICH at 24-48 hours (according to ECASS III criteria), major neurological improvement at 24 hours (National Institutes of Health Stroke Scale [NIHSS] score of 0 at 24 hours or a reduction in NIHSS score of ≥ 4 points at 24 hours compared to baseline), death within 3 months

Baseline Characteristics

Tenecteplase

(n=549)

Alteplase

(n=551)

Age, years

Female

Symptoms on awakening

Major intracranial vessel occlusion

Diagnosis of hypertension

Smoker

History of stroke or transient ischemic attack

Results

Endpoint

Tenecteplase

(n=549)

Alteplase

(n=551)

Odds Ratio (95% confidence interval)

p-value

mRS Score 0 to 1 at 3 months

Any ICH at 24 to 48 hours

50 (9%)

Symptomatic ICH at 24 to 48 hours

Major neurological improvement at 24 hours 

Death within 3 Months 

Adverse Events

Only serious side effects were reported.

Adverse events were reported to have a similar frequency in both treatment groups: 145 vs 141 for tenecteplase and alteplase, respectively.

The most frequent adverse event was any ICH at 9% of patients in both groups.

Study Author Conclusions

Tenecteplase was not superior to alteplase and showed a similar safety profile. Most patients enrolled in this study had mild stroke. Further trials are needed to establish the safety and efficacy in patients with severe stroke and whether tenecteplase is non-inferior to alteplase.

InpharmD Researcher Critique

Alteplase Versus Tenecteplase for Thrombolysis After Ischaemic Stroke (ATTEST): A Phase 2, Randomised, Open-Label, Blinded Endpoint Study 

Design

Single-center, phase 2, prospective, randomized, open-label, blinded end-point evaluation study

N= 104

Objective

To assess the efficacy and safety of tenecteplase versus alteplase within 4.5 hours of stroke onset

Study Groups

Alteplase group (n= 52) 

Tenecteplase group (n= 52) 

Inclusion Criteria

Clinically diagnosed supratentorial acute ischemic stroke with a measurable deficit on the National Institutes of Health stroke scale (NIHSS), within 4.5 h of symptom onset, aged 18 years or older, living independently pre-stroke, and eligible for intravenous thrombolysis according to clinical guidelines

Exclusion Criteria

Estimated glomerular filtration rate < 30mL/min, allergic to iodinated contrast, evidence of intracranial hemorrhage or significant non-stroke intracranial pathology (including central nervous system neoplasm, aneurysm or arteriovenous malformation) on pre-treatment computed tomography (CT), established hypodensity on pre-treatment brain CT of more than one-third of the middle cerebral artery territory or Alberta Stroke Programme Early CT (ASPECT) Score <4, hypodensity consistent with recent cerebral ischemia other than the presenting event, very severe stroke, systolic blood pressure (SBP) > 185 or diastolic blood pressure (DBP) > 110 mm Hg, or aggressive management (intravenous pharmacotherapy) necessary to reduce BP to these limits, risk of bleeding, dependent (modified Rankin Scale [mRS] 3 to 5) pre-stroke, blood glucose <2 mmol/L (36 mg/dL) or >18 mmol/L (324 mg/dL), and pregnancy

Methods

Eligible patients were randomized (1:1) to receive either alteplase (0.9 mg per kg to a maximum 90 mg, with 10% of dose as initial bolus, followed by 90% in a 1 h infusion) or tenecteplase (0.25 mg per kg, to a maximum 25 mg as a single bolus). The NIHSS assessment was completed at baseline, 24-48 h post-treatment, 72 h post-treatment, and 7 days post-treatment. CT perfusion and CT angiography were done at baseline with follow-up scans at 24-48h post thrombolysis.

Duration

Screening: January 1, 2012 to September 7, 2013

Follow-up: 90 days

Outcome Measures

Primary outcome: percentage of penumbra salvaged (CT perfusion-defined penumbra volume at baseline minus CT infarct volume at 24–48 hours)

Secondary outcomes: infarct volume on 24 to 48 hour non-contrast CT (whole brain infarct volume and co-registered infarct volume); recanalization (mRS score 0 to 1) at 30 days and 90 days; recanalization at 24 to 48 hours (Thrombolysis in Myocardial Infarction grade 2 to 3); early neurological improvement (reduction in NIHSS of ≥ 8 or NIHSS score of 0 or 1 at 24 to 48 hours post-treatment) at 24 hours; mean home time spent at non-institutional private residence at 90 days; mortality at 90 days

Safety outcomes: proportion of patients with symptomatic intracerebral hemorrhage (SICH) at 24 to 48 hours post-treatment based on Safe Implementation of Thrombolysis In Stroke Monitoring Study (SITS-MOST) criteria; proportion of patients with SICH as defined in European Cooperative Acute Stroke Study (ECASS) II; proportion of patients with any intracerebral hemorrhage

Baseline Characteristics

Tenecteplase

(n= 47)

Alteplase

(n= 49)

Age, years

Male

Dominant hemisphere stroke

Previous stroke or transient ischemic attack

Hypertension

Current Smoker 

Median baseline NIHSS (interquartile range [IQR])

Onset to treatment time, minutes

Mean ± standard deviation

Median (IQR)

Time between initial and follow-up imaging, hours

Door to needle time, minutes

184 ± 44

180 (156 to 215)

28.5 ± 7.1

42 ± 17

192 ± 45

200 (160–220)

27.3 ± 7.5

38 ± 19

Results

Endpoint

Tenecteplase 

(n= 47)

Alteplase 

(n= 49)

Odds ratio (95% confidence interval [CI])

95% CI for mean difference; p-value 

Percentage penumbral salvaged at 24 to 48 hours

Infarct volume

Co-registed final infarct volume 24 to 48 hours, mL 

Total infarct volume at 24 to 48 hours, mL

50 ± 62

75 ± 101

47 ± 62

66 ± 91

-

-

-19.4 to 19.6; 1

-25.6 to 35.4; 0.75

Recanalization

24 to 48 hours

30 days

90 days 

21/32 (66%)

7 (15%)

13 (28%) 

26/35 (74%)

7 (15%)

10 (20%) 

0.6 (0.2 to 1.8)

1.1 (0.3 to 3.5)

1.8 (0.6 to 5.5)

0.38

0.89

0.28

Early neurological improvement at 24 hours

Days at home by 90 days 

Mortality at 90 days

Intracranial hemorrhage

Any intracranial hemorrhage

SICH (SITS-MOST definition)

SICH (ECASS II definition)

n= 52

8 (15%)

1 (2%)

3 (6%)

n= 51

14 (27%)

2 (4%)

4 (8%)

0.4 (0.2 to 1.2)

0.4 (0.04 to 5.1)

0.6 (0.1 to 3.2)

0.09

0.5

0.59

Adverse Events

Up to day 90, 32 serious adverse events (62%) were noted in 22 (42%) patients given tenecteplase and 16 (31%) patients given alteplase, including intracerebral hemorrhage. The most common serious adverse event in the tenecteplase and alteplase groups was pneumonia (4%) and intracerebral hemorrhage (10%), respectively.

Study Author Conclusions

Neither radiological nor clinical outcomes differed significantly with IV tenecteplase 0.25 mg/kg compared with alteplase 0.9 mg/kg, the present standard of care. The study did not note any difference in the primary endpoint of penumbral salvage, and safety outcomes did not differ, notably intracerebral hemorrhages of all kinds, and parenchymal hematomas, the complication most strongly associated with treatment-related neurological deterioration.

InpharmD Researcher Critique

This was a single-center study conducted in Scotland with a small sample size. Limitations of the study include the use of non-contrast CT to quantify final infarct given that the extent of the ischaemic lesion often remains poorly defined at 24 h with this method.

A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke

Design

Phase 2b trial, randomized, open-label, blinded trial

N= 75

Objective

To compare the standard dose of alteplase with two different doses of tenecteplase for treatment of acute ischemic stroke

Study Groups

Alteplase (n= 25)

Tenecteplase 0.1 mg/kg (n= 25)

Tenecteplase 0.25 mg/kg (n= 25)

Inclusion Criteria

Age ≥ 18 years with first-ever hemispheric ischemic stroke; score > 4 on National Institutes of Health Stroke Scale (NIHSS) and premorbid score < 2 on the modified Rankin scale; presence of intracranial occlusion in the anterior cerebral, middle cerebral, or posterior cerebral artery on computed tomography (CT); hemispheric perfusion lesion at least 20% greater than infarct-core lesion with volume at least 20 mL; infarct-core lesion < 1/3 the territory of the middle cerebral artery or < 1/2 the territory of the anterior cerebral or posterior cerebral artery

Exclusion Criteria

Contraindication to alteplase, presence of internal carotid artery and vertebrobasilar occlusions

Methods

Following CT perfusion and angiographic imaging, patients were randomized (1:1:1) to receive alteplase (0.9 mg/kg with the first 10% administered as an initial bolus and remainder over 1-hour period; maximum of 90 mg), tenecteplase 0.1 mg/kg (administered as single bolus; maximum of 10 mg) or tenecteplase 0.25 mg/kg (administered as single bolus; maximum of 25 mg). Then, evaluated for efficacy and safety 24 hours after treatment. 

Duration

24 hours

Outcome Measures

Primary outcomes: percentage of perfusion lesion reperfused 24 hours after treatment, clinical improvement at 24 hours (measured by change on NIHSS score from before treatment to 24 hours after treatment)

Secondary outcomes: infarct growth at 24 hours and 90 days, vessel recanalization at 24 hours, major neurologic improvement at 24 hours (reduction from baseline ≥ 8 points on NIHSS), excellent recovery at 90 days (score of 0 or 1 on modified Rankin scale), excellent or good recovery at 90 days (score of 0-2)

Safety outcomes: occurrence of large parenchymal hematoma (> 30% of infarct volume), any size parenchymal hematoma, and symptomatic intracranial hemorrhage; poor outcome or death at 90 days (score of 5 or 6, respectively on modified Rankin scale)

Baseline Characteristics

Alteplase

(n= 25)

Tenecteplase 0.1 mg/kg

(n= 25)

Tenecteplase 0.25 mg/kg

(n= 25)

Age, years

Male

Hypertension

Current medications

Antiplatelet agent

Anticoagulant

11 (44%)

1 (4%)

11 (44%)

1 (4%)

12 (48%)

1 (4%)

Time to treatment, hours

Median volume of infarct core (interquartile range [IQR])

Median volume of perfusion lesion (IQR)

Results

Endpoint

Alteplase

(n= 25)

Tenecteplase

(n= 50)

p-value

Reperfusion at 24 hours, %

Improvement in NIHSS score between at 24 hours

Median infarct growth (IQR), mL

24 hours

90 days

14 (0 to 144)

12 (-1 to 113)

3 (-1 to 121)

2 (-2 to 133)

0.04

0.01

Recanalization at 24 hours

Complete

Complete or partial

8/22 (36%)

15/22 (68%)

28/48 (58%)

42/48 (88%)

0.09

0.05

Major neurologic improvement at 24 hours

9 (36%)

32 (64%)

0.02

Excellent recovery at 90 days

Excellent or good recovery at 90 days

Poor outcome at 90 days

Death

Large parenchymal hematoma

Any parenchymal hematoma

Symptomatic intracranial hematoma

Three patients died in the lower dose tenecteplase group and 1 patient died in the higher dose group. Two deaths in the alteplase group were due to massive hemispheric infarction and one was due to symptomatic intracranial hemorrhage. One death in the lower dose tenecteplase group was due to intracranial hemorrhage, one to aspiration pneumonia, and one to a late second stroke. The death in the higher dose tenecteplase group was due to multiple coexisting conditions.

Based on a dose-tier analysis, the higher dose of tenecteplase was associated with improvement on all imaging efficacy outcomes compared to alteplase. There were 72% of patients who had excellent recovery in the higher dose tenecteplase group compared to 40% in the alteplase group (p= 0.02). Patients in the lower dose tenecteplase group had greater clinical improvement at 24 hours compared to patients receiving alteplase (p= 0.04), but other efficacy outcomes were equivalent between the two groups.

Higher reperfusion and recanalization occurred at higher doses of tenecteplase, which led to greater clinical improvement at 24 hours and increase in the number of patients with excellent recovery in the higher dose group at 90 days (p= 0.01).

Study Author Conclusions

Tenecteplase was associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging.

InpharmD Researcher Critique

The study is funded by Boehringer Ingelheim which supplies tenecteplase. Patients were chosen based on those most likely to benefit from treatment which excluded a large number of other patients who may benefit from thrombolysis. This limitation was due to being a phase 2b study.

Tenecteplase Versus Alteplase Before Thrombectomy for Ischemic Stroke

Design

Multicenter, prospective, randomized, open-label, blinded-outcome trial

N= 204

Objective

To compare tenecteplase with alteplase in establishing reperfusion in patients before endovascular thrombectomy when administered within 4.5 hours after onset of symptoms

Study Groups

Tenecteplase (n= 101)

Alteplase (n= 101)

Inclusion Criteria

Able to undergo intravenous thrombolysis within 4.5 hours after onset of ischemic stroke; cerebral vascular occlusion on computed tomography (CT) angiography of the internal carotid artery, first segment of middle cerebral artery, second segment of middle cerebral artery, or basilar artery; treatment to retrieve intra-arterial clot able to be completed within 6 hours after stroke onset

Entry criteria requiring CT-perfusion mismatch for anterior circulation stroke was removed after approximately 80 patients had been enrolled

Exclusion Criteria

Methods

Patients were randomized (1:1) to receive intravenous tenecteplase (0.25 mg/kg; maximum dose of 25 mg) or alteplase (0.9 mg/kg; maximum dose of 90 mg). An angiogram was conducted following thrombectomy; however, if no lesion was suitable for thrombectomy, the endovascular procedure was terminated.

Non-inferiority for the primary outcome was established if the lower boundary of the 95% confidence interval was > -2.3 percentage points for the difference of tenecteplase versus alteplase.

Duration

Enrollment: March 2015 to October 2017

Outcome Measures

Primary outcome: substantial reperfusion (restoration of blood flow to > 50% of involved territory or absence of retrievable thrombus in target vessel at the time of initial angiographic assessment) assessed with the modified Treatment in Cerebral Ischemia classification (scores range from 0 [no flow] to 3 [normal flow])

Secondary outcomes: modified Rankin scale score at 90 days, early neurologic improvement (reduction of ≥ 8 points or score of 0 or 1 on National Institute of Health Stroke Scale [NIHSS] at 72 hours)

Safety outcomes: death due to any cause, symptomatic intracranial hemorrhage, parenchymal hematoma

Baseline Characteristics

Tenecteplase (n= 101)

Alteplase (n= 101)

Age, years

Male

Median NIHSS score (interquartile range [IQR])

Cause of stroke

Cardioembolic occlusion

Large-artery occlusion

46 (46%)

21 (21%)

54 (53%)

18 (18%)

Median time from stroke onset to hospital arrival (IQR), minutes

60 (44 to 89)

72 (53 to 104)

Median time from stroke onset to initiation of intravenous thrombolysis (IQR), minutes

125 (102 to 156)

134 (104 to 176)

Median time from initiation of intravenous thrombolysis to arterial puncture (IQR), minutes

43 (25 to 57)

42 (30 to 63)

Median time from initiation of intravenous thrombolysis to initial angiographic assessment (IQR), minutes

54 (34 to 67)

Interhospital transfer for thrombectomy

27 (27%)

Site of vessel occlusion

Internal carotid artery

Basilar artery

Middle cerebral artery

First segment

Second segment

24 (24%)

3 (3%)

59 (58%)

15 (15%)

24 (24%)

3 (3%)

60 (59%)

14 (14%)

Median volume at initial imaging (IQR), mL

Ischemic core

Perfusion lesion

14 (0 to 33)

145 (105 to 175)

11 (0 to 24)

134 (103 to 170)

Results

Endpoint

Tenecteplase (n= 101)

Alteplase (n= 101)

Effect size (95% confidence interval); p-value

Substantial reperfusion

Difference

Adjusted incidence ratio

Adjusted odds ratio

22 (22%)

-

-

-

10 (10%)

-

-

-

-

12 (2 to 21); 0.002

2.2 (1.1 to 4.4); 0.03

2.6 (1.1 to 5.9); 0.02

Median score on modified Rankin scale at 90 days (IQR)

Functionally independent outcome

Adjusted incidence ratio

Adjusted odds ratio

Excellent outcome

Adjusted incidence ratio

Adjusted odds ratio

2 (0 to 3)

65 (64%)

-

-

52 (51%)

-

-

3 (1 to 4)

52 (51%)

-

-

43 (43%)

-

-

1.7 (1 to 2.8); 0.04

-

1.2 (1 to 1.5); 0.06

1.8 (1 to 3.4); 0.06

-

1.2 (0.9 to 1.6); 0.2

1.4 (0.8 to 2.6); 0.23

Early neurologic improvement

Adjusted incidence ratio

Adjusted odds ratio

72 (71%)

-

-

69 (68%)

-

-

-

1 (0.9 to 1.2); 0.7

1.1 (0.6 to 2.1); 0.7

Death

Adjusted risk ratio

Adjusted odds ratio

10 (10%)

-

-

18 (18%)

-

-

-

0.5 (0.3 to 1); 0.049

0.4 (0.2 to 1.1); 0.08

Symptomatic intracerebral hemorrhage

Risk ratio

Odds ratio

1 (1%)

-

-

1 (1%)

-

-

-

1 (0.1 to 15.9); 0.99

1 (0.1 to 16.2); 0.99

Parenchymal hematoma

Risk ratio

Odds ratio

6 (6%)

-

-

5 (5%)

-

-

-

1.2 (0.4 to 3.8); 0.76

1.2 (0.4 to 4.1); 0.76

Study Author Conclusions

InpharmD Researcher Critique

These results only apply to patients with ischemic stroke and large-vessel occlusion eligible for thrombolysis, as reported by the authors. Since these patients make up a small proportion of patients with ischemic stroke, it is necessary to determine the efficacy of alteplase versus tenecteplase for patients who may not have large-vessel occlusions. 

Notably, the exclusion criteria of the modified Rankin scale score ≥3 mentioned in the study was different from the modified Rankin scale score ≥4 listed in the Supplementary Appendix without clear explanations. 

Tenecteplase Versus Alteplase After Acute Ischemic Stroke at High Age

Design

Sub-study of a multicenter, randomized, open-label, blinded endpoint, phase 3 trial

N= 273

Objective

To compare efficacy and safety of tenecteplase and alteplase in patients ≥ 80 years

Study Groups

Tenecteplase (n= 130)

Alteplase (n= 143)

Inclusion Criteria

Patients from the NOR-TEST trial ≥ 80 years

Exclusion Criteria

Not explicitly stated

Methods

This was a sub-study of the Norwegian Tenecteplase Stroke Trial (NOR-TEST). Patients received either tenecteplase 0.4 mg/kg or alteplase 0.9 mg/kg.

Outcome Measures

Primary outcome: excellent functional outcome (modified Rankin Scale [mRS] 0-1 at 3 months)

Secondary outcomes: symptomatic intracranial hemorrhage (sICH) occurring within 24-48 hours, death within 3 months, major neurological improvement at 24 hours (either National Institute of Health Stroke Scale [NIHSS] score 0 or reduction of NIHSS ≥ 4 points at 24 hours compared with baseline score)

Baseline Characteristics

Tenecteplase (n= 130)

Alteplase (n= 143)

Age, years

Female

Final diagnosis

Ischemic stroke

Stroke mimic

118 (90.8%)

12 (9.2%)

125 (87.4%)

18 (12.6%)

0.44

0.44

Risk factors

Hypertension

Ischemic heart disease

Previous stroke or TIA

82 (63%)

18 (13.8%)

23 (17.7%)

88 (61.5%)

32 (22.3%)

31 (21.7%)

0.8

0.09

0.45

NIHSS on admission

TIA: transient ischemic attack

Results

Tenecteplase (n= 130)

Alteplase (n= 143)

Odds ratio (95% confidence interval); p-value

Intention-to-treat analysis

mRS score 0-1 at 3 months

Major clinical improvement at 24 hours

sICH within 48 hours

Death within 3 months

56 (43.1%)

46/115 (40%)

11 (8.5%)

18 (14.3%)

57 (39.9%)

47/131 (35.9%)

10 (7%)

21 (15.3%)

1.14 (0.7 to 1.85); 0.59

1.19 (0.71 to 2); 0.51

1.23 (0.5 to 3); 0.65

0.93 (0.47 to 1.84); 0.84

Per-protocol analysis

mRS score 0-1 at 3 months

Major clinical improvement at 24 hours

sICH within 48 hours

Death within 3 months

52 (44.1%)

48 (40.7%)

11 (9.3%)

17 (14.9%)

43 (34.4%)

43 (34.4%)

10 (8%)

20 (16.8%)

1.5 (0.9 to 2.52); 0.12

1.39 (0.82 to 2.34); 0.22

1.18 (0.48 to 2.9); 0.71

0.88 (0.44 to 1.78); 0.73

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Tenecteplase, given at a dose of 0.4 mg/kg in this NOR-TEST sub-study about patients ≥ 80 years has the same efficacy and safety as alteplase. Therefore, high age should not be a reason to discourage from treatment with tenecteplase in acute ischemic stroke.

InpharmD Researcher Critique

This study shows the efficacy and safety of tenecteplase are similar in elderly patients; however, the NOR-TEST trial only included patients living independently, which may have prevented inclusion of more severe patients with cognitive or functional impairments and severe comorbidities.