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TIMELESS: Tenecteplase in Stroke Patients Between 4.5 and 24 Hours

Sponsor
Genentech, Inc. (Industry)
Overall Status
Recruiting
CT.gov ID
NCT03785678
Collaborator
(none)
456
Enrollment
129
Locations
2
Arms
42
Anticipated Duration (Months)
3.5
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Biological: Tenecteplase
  • Other: Placebo
 Phase 3

Study Design

Study Type:
Interventional
Anticipated Enrollment :
456 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase III, Prospective, Double-blind, Randomized, Placebo-controlled Trial of Thrombolysis in Imaging-eligible, Late-window Patients to Assess the Efficacy and Safety of Tenecteplase (TIMELESS)
Actual Study Start Date :
Mar 2, 2019
Anticipated Primary Completion Date :
Sep 1, 2022
Anticipated Study Completion Date :
Sep 1, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Tenecteplase

Patients in this arm will receive Tenecteplase (0.25 mg/kg, maximum 25 mg) administered as a single bolus injection over 5 seconds.

Biological: Tenecteplase
The investigational medicinal product (IMP) for this study is tenecteplase. The recommended total dose for this study is weight-based with 0.25 mg of tenecteplase per kg, not exceeding a maximum dose of 25 mg. A single bolus dose should be administered over 5 seconds based on patient weight.
Placebo Comparator: Placebo

Patients in this arm will receive placebo administered as a single bolus injection over 5 seconds.

Other: Placebo
Placebo is being used as the comparator since a thrombolytic is only FDA-approved in the United States for use out to 3 hours, and the standard of care guidelines support use out to 4.5 hours.

Outcome Measures

Primary Outcome Measures

  1. Ordinal modified Rankin scale (mRS) score [Day 90]

    The Efficacy of Tenecteplase compared to placebo is evaluated in terms of Ordinal mRS score at day 90.

Secondary Outcome Measures

  1. Proportion of patients with functional independence [Day 90]

    The efficacy of Tenecteplase is evaluated in terms of proportion of patients with functional independence, defined as an mRS of 0-2, at Day 90

  2. Proportion of patients with angiographic reperfusion [Day 1]

    The efficacy of Tenecteplase is evaluated in terms of proportion of patients with angiographic reperfusion at completion of angiographic procedure (endovascular patients only).

  3. Median NIHSS score [Day 90]

    The efficacy of Tenecteplase is evaluted in terms of Median NIHSS score at Day 90.

  4. Proportion of patients with a Barthel Index (BI) score >=95 [Day 90]

    The efficacy of Tenecteplase is evaluated in terms of Proportion of patients with a BI score >=95 at Day 90.

  5. Proportion of patients with good recovery based on the Glasgow Outcome Scale (GOS) at Day 90 [Day 90]

    The efficacy of Tenecteplase is evaluated in terms of the proportion of patients with good recovery based on the GOS at Day 90.

  6. Proportion of patients with reperfusion at 24 hours post-randomization [Day 2]

    The efficacy of Tenecteplase is evaluated in terms of proportion of patients with reperfusion at 24 hours post-randomization, defined as >90% reduction in Tmax>6s lesion volume

  7. Proportion of patients with recanalization at 24 hours post-randomization [Day 2]

    The efficacy of Tenecteplase is evaluated in terms of proportion of patients with recanalization at 24 hours post-randomization, defined as complete or partial recanalization on CT angiography (CTA)/magnetic resonance angiography (MRA).

  8. Number of patients with symptomatic intracranial hemorrhage (sICH a) [Day 2]

    The safety profile of Tenecteplase is evaluated in terms of number of patients with sICH within 36 hours

  9. Incidence and severity of adverse events [From baseline up to day 90]

    The safety profile of Tenecteplase is evaluated in terms of incidence and severity of adverse events.

  10. Mortality rate up to Day 30 and Day 90 [Day 30 and Day 90]

    The safety profile of Tenecteplase is evaluated in terms of mortality rate up to Day 30 and Day 90

  11. Proportion of patients with parenchymal hematoma type 2 (PH2) at the 72-96 hour visit [Day 3]

    The safety profile of Tenecteplase is evaluated in terms of proportion of patients with PH2 at the 72-96 hour visit

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

  • Patient/legally authorized representative has signed the Informed Consent Form

  • Age >= 18 years

  • AIS symptom onset within 4.5 to 24 hours Signs and symptoms consistent with the diagnosis of an acute anterior circulation ischemic stroke involving occlusion of the ICA, M1, or M2 vessels

  • Functionally independent (mRS 0-2) prior to stroke onset

  • Baseline NIHSS >=5 and that remains >=5 immediately prior to randomization

  • Neuroimaging: ICA or M1, M2 occlusion (carotid occlusions can be cervical or intracranial, with or without tandem MCA lesions) by magnetic resonance angiography (MRA) or computed tomography angiography (CTA) AND target mismatch profile on CT perfusion or MR perfusion (ischemic core volume <70 mL, mismatch ratio is >=1.8 and mismatch volume is >= 15 mL)

  • The mismatch volume is determined by FDA-approved imaging software in real time based on the difference between the ischemic core lesion volume and the Tmax>6s lesion volume. If both a CT perfusion and a multimodal MRI scan are performed prior to enrollment, the later of the 2 scans is assessed to determine eligibility. Only an intracranial MRA is required for patients screened with MRA; cervical MRA is not required. Cervical and intracranial CTA are typically obtained simultaneously in patients screened with CTA, but only the intracranial CTA is required for enrollment.

Alternative neuroimaging:

  • If CTA (or MRA) is technically inadequate: Tmax>6s perfusion deficit consistent with an ICA or M1, M2 occlusion AND target mismatch profile (ischemic core volume <70 mL, mismatch ratio >= 1.8 and mismatch volume >= 15 mL as determined by RAPID software)

  • If magnetic resonance perfusion (MRP) is technically inadequate: ICA or M1, M2 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA (or CTA, if MRA is technically inadequate and a CTA was performed within 60 minutes prior to the MRI) AND diffusion-weighted imaging (DWI) lesion volume <=25 mL for an M1 or ICA occlusion and =<15 mL for an M2 occlusion

  • If CTP is technically inadequate: patient can be screened with MRI and randomized if neuroimaging criteria are met.

  • Ability to comply with the study protocol, in the investigator's judgment

Exclusion Criteria:

General

  • Current participation in another investigational drug or device study

  • Active internal bleeding

  • Known hypersensitivity or allergy to any ingredients of tenecteplase

  • Known bleeding diathesis

  • Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; recent oral anticoagulant therapy with INR >1.7

  • Use of one of the new oral anticoagulants within the last 48 hours (dabigatran, rivaroxaban, apixaban, edoxaban)

  • Pregnant

  • Intracranial neoplasm (except small meningioma), arteriovenous malformation, or aneurysm

  • Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS

  • Severe, uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure > 110 mmHg)

  • For participants with suspected coagulopathy, platelet count must be checked prior to randomization and participant is excluded if baseline platelet count <100,000/microL

  • Baseline blood glucose >400 mg/dL (22.20 mmol/L)

  • Baseline blood glucose <50 mg/dL needs to be normalized prior to randomization

  • Clot retrieval attempted using a neurothrombectomy device prior to randomization

  • Intracranial or intraspinal surgery or trauma within 2 months

  • Treatment with a thrombolytic within the last 3 months prior to randomization

  • Other serious, advanced, or terminal illness (investigator judgment) with life expectancy less than 6 months

  • Pre-existing medical, neurological, or psychiatric disease that would confound the neurological or functional evaluations

  • History of cerebrovascular accident in the last 90 days

  • Presumed septic embolus; suspicion of bacterial endocarditis

  • Any other condition that, in the opinion of the investigator, precludes an endovascular procedure or poses a significant hazard to the patient if an endovascular procedure was to be performed

Imaging

  • Unable to undergo a contrast brain perfusion scan with either MRI or CT

  • Extensive early ischemic change (hypodensity) on non-contrast CT estimated to be >1/3 MCA territory, or significant hypodensity outside the Tmax>6s perfusion lesion that invalidates mismatch criteria (if patient is enrolled based on CT perfusion criteria)

  • Significant mass effect

  • Acute symptomatic arterial occlusions in more than one vascular territory confirmed on CTA/MRA (e.g., bilateral MCA occlusions, or an MCA and a basilar artery occlusion)

  • Evidence of intracranial tumor (except small meningioma) acute intracranial hemorrhage, neoplasm, or arteriovenous malformation

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of Alabama at Birmingham Birmingham Alabama United States 35294-3300
2 Banner Desert Medical Center Mesa Arizona United States 85202
3 University of Arkansas For Medical Sciences Little Rock Arkansas United States 72205
4 Kaiser Permanente - Anaheim (E. La Palma) Anaheim California United States 92806
5 Sutter Auburn Faith Hospital Auburn California United States 95602
6 Mills-Peninsula Medical Center Burlingame California United States 94010
7 John Muir Health, Concord Medical Center Concord California United States 94520
8 Sutter Davis Hospital Davis California United States 95616
9 Kaiser Permanente - Fontana Fontana California United States 92335
10 Adventist Health Glendale Glendale California United States 91206
11 Kaiser Permanente South Bay Medical Center Harbor City California United States 90710
12 UCSD Medical Center - La Jolla La Jolla California United States 92037
13 CHA Hollywood Presbyterian Medical Center Los Angeles California United States 90027
14 Kaiser Permanente Los Angeles Los Angeles California United States 90027
15 University of Southern California Medical Center Los Angeles California United States 90033
16 Cedars-Sinai Medical Center Los Angeles California United States 90048
17 Cedars-Sinai Marina Del Rey Hospital Marina Del Rey California United States 90292
18 Kaiser Permanente - Ontario Ontario California United States 91761
19 Stanford University Medical Center Palo Alto California United States 94304
20 Sutter Roseville Medical Center Roseville California United States 95661
21 Sutter Medical Group, Neurology Sacramento California United States 95816
22 UCSD - Hillcrest; Hillcrest Medical Center San Diego California United States 92103
23 CPMC - Van Ness Campus San Francisco California United States 94109
24 CPMC - Davies Campus San Francisco California United States 94114
25 UCSF San Francisco California United States 94143-0106
26 Adventist Health-Simi Valley Simi Valley California United States 93065
27 Torrance Memorial Medical Center Torrance California United States 90505
28 John Muir Medical Center-Walnut Creek Walnut Creek California United States 94598
29 Swedish Medical Center Englewood Colorado United States 80110
30 Hartford Hospital Hartford Connecticut United States 06102
31 The Hospital of Central CT New Britain Connecticut United States 06050
32 The William Backus Hospital Norwich Connecticut United States 06360
33 University of Florida Health at Shands Gainesville Florida United States 32608
34 Memorial Healthcare System - Memorial Regional Hospital Hollywood Florida United States 33021
35 Baptist Medical Center - Jacksonville Jacksonville Florida United States 32207-8202
36 Baptist Medical Center-South Jacksonville Florida United States 32258
37 Jackson Memorial Hospital Miami Florida United States 33136
38 Jackson South Medical Center Miami Florida United States 33157
39 Emory University; Grady Memorial Hospital Atlanta Georgia United States 30322
40 The Queen's Medical Center Honolulu Hawaii United States 96813
41 Northwestern University Chicago Illinois United States 60611
42 Advocate Christ Medical Center Oak Lawn Illinois United States 60453
43 Advocate Lutheran General Hospital Park Ridge Illinois United States 60068
44 St. Catherine Hospital East Chicago Indiana United States 46312
45 Parkview Regional Medical Center Fort Wayne Indiana United States 46845
46 St. Mary Medical Center Hobart Indiana United States 46432
47 Community Hospital Munster Indiana United States 46321
48 Uni of Kansas Medical Center Kansas City Kansas United States 66160
49 Baptist Health Lexington Lexington Kentucky United States 40503
50 Sinai Hospital of Baltimore Baltimore Maryland United States 21215
51 Johns Hopkins Baltimore Maryland United States 21287
52 Howard County General Hospital Columbia Maryland United States 21044
53 Massachusetts General Hospital Boston Massachusetts United States 02114
54 Univ of Michigan Medical Ctr Ann Arbor Michigan United States 48109-0718
55 Henry Ford Macomb Hospital - Clinton Township Clinton Township Michigan United States 48038
56 Henry Ford Hospital Detroit Michigan United States 48202
57 Ascension St. John Hospital Detroit Michigan United States 48236
58 McLaren Flint Flint Michigan United States 48532
59 Spectrum Health Hospitals Grand Rapids Michigan United States 49503
60 ProMedica Monroe Regional Hospital Monroe Michigan United States 48162
61 Fairview Ridges Hospital Burnsville Minnesota United States 55337
62 Fairview Southdale Edina Minnesota United States 55435
63 U of Minnesota MedCtr Fairview Minneapolis Minnesota United States 55455
64 Sanford Worthington Medical Center Worthington Minnesota United States 56187
65 Saint Luke's Hospital of Kansas City Kansas City Missouri United States 64111
66 Saint Luke's East Hospital Lee's Summit Missouri United States 64086
67 Washington University Saint Louis Missouri United States 63128
68 JFK Neuroscience Institute Edison New Jersey United States 08820
69 Hackensack University Medical Center Hackensack New Jersey United States 07601
70 Atlantic Health System - Newton Medical Center Newton New Jersey United States 07860
71 Palisades Medical Centre North Bergen New Jersey United States 07047
72 Atlantic Health System - Chilton Medical Center Pompton Plains New Jersey United States 07444
73 Atlantic Health System - Overlook Medical Center Summit New Jersey United States 07901
74 Capital Health Regional Medical Center Trenton New Jersey United States 08638
75 Buffalo General Medical Center Buffalo New York United States 14203
76 Millard Fillmore Suburban Hospital Buffalo New York United States 14221
77 Columbia University Medical Center New York New York United States 10032
78 Mission Hospitals Inc Asheville North Carolina United States 28803
79 Guilford Neurologic Research Greensboro North Carolina United States 27405
80 Vidant Medical Center Greenville North Carolina United States 27834
81 Univ of Cincinnati Cincinnati Ohio United States 45219
82 Fairview General Hospital Cleveland Ohio United States 44111
83 Cleveland Clinic Cleveland Ohio United States 44195
84 Riverside Methodist Hospital; Cancer Services Columbus Ohio United States 43214-1419
85 Grant Medical Center Columbus Ohio United States 43215
86 Doctors Hospital Columbus Ohio United States 43228
87 Hillcrest Hospital Mayfield Heights Ohio United States 44124
88 ProMedica Toledo Hospital Toledo Ohio United States 43606
89 Ascension St. John Tulsa Oklahoma United States 74104
90 Tuality Healthcare Hillsboro Oregon United States 97123
91 Providence Portland Medical Center Portland Oregon United States 97213
92 Adventist Health Portland Portland Oregon United States 97216
93 Providence Saint Vincent's Medical Center Portland Oregon United States 97225
94 Oregon Health and Science University Portland Oregon United States 97239
95 Portland Va Medical Center/Ohsu Portland Oregon United States 97239
96 UPMC East Hospital Monroeville Pennsylvania United States 15146
97 Penn Presbyterian Medical Center Philadelphia Pennsylvania United States 19104
98 Uni of Pennsylvania Philadelphia Pennsylvania United States 19104
99 Pennsylvania Hospital Philadelphia Pennsylvania United States 19107
100 University of Pittsburgh Medical Center Pittsburgh Pennsylvania United States 15213
101 UPMC Mercy Pittsburgh Pennsylvania United States 15219
102 UPMC Passavant Hospital Pittsburgh Pennsylvania United States 15237
103 Rhode Island Hospital Providence Rhode Island United States 02903
104 Medical University of South Carolina Charleston South Carolina United States 29425
105 Sanford Neurology Clinic Sioux Falls South Dakota United States 57104
106 Chattanooga Center for Neurologic Research Chattanooga Tennessee United States 37404
107 CHI Memorial Hospital Chattanooga Tennessee United States 37404
108 Saint Thomas Rutherford Hospital Murfreesboro Tennessee United States 37129
109 Saint Thomas Health Nashville Tennessee United States 37205
110 Saint Thomas Midtown Hospital Nashville Tennessee United States 37232
111 Vanderbilt University Nashville Tennessee United States 37232
112 Dell Seton Medical center at the University of Texas Austin Texas United States 78701
113 Seton Medical Center Austin Austin Texas United States 78705
114 Valley Baptist Medical Center-Brownsville Brownsville Texas United States 78520
115 Texas Stroke Institute Dallas Texas United States 75075
116 Baylor University Medical Center Dallas Texas United States 75231
117 Medical City Denton Denton Texas United States 76210
118 Valley Baptist Medical Center Harlingen Texas United States 78550
119 University of Texas at Houston; Neurology Houston Texas United States 77030
120 Ascension Seton Hays Kyle Texas United States 78640
121 Medical City Lewisville Lewisville Texas United States 75057
122 Ascension Seton Williamson Round Rock Texas United States 78665
123 University of Texas Health Science Center at San Antonio San Antonio Texas United States 78229
124 Intermountain Healthcare Salt Lake City Utah United States 84107
125 University of Virginia Charlottesville Virginia United States 22906
126 University of Wisconsin Madison Wisconsin United States 53792
127 Uni of Alberta Edmonton Alberta Canada T6G 2G3
128 Hamilton General Hospital; Pharmacy Hamilton Ontario Canada L8L 2X2
129 Montreal Neurological Inst; Clinical Research Unit Montreal Quebec Canada H3A 2B4

Sponsors and Collaborators

  • Genentech, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT03785678
Other Study ID Numbers:
  • ML40787
First Posted:
Dec 24, 2018
Last Update Posted:
Aug 5, 2022
Last Verified:
Aug 1, 2022
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:
Tenecteplase

Study Results

No Results Posted as of Aug 5, 2022