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History of Changes for Study: NCT03785678
Tenecteplase in Stroke Patients Between 4 and 24 Hours (TIMELESS)
Latest version (submitted November 21, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 December 20, 2018 None (earliest Version on record)
2 June 26, 2019 Recruitment Status, Contacts/Locations and Study Status
3 July 26, 2019 Contacts/Locations, Outcome Measures, Study Status and Eligibility
4 August 22, 2019 Contacts/Locations and Study Status
5 September 20, 2019 Study Status and Contacts/Locations
6 October 17, 2019 Contacts/Locations and Study Status
7 November 13, 2019 Contacts/Locations and Study Status
8 December 11, 2019 Contacts/Locations and Study Status
9 January 9, 2020 Contacts/Locations and Study Status
10 February 7, 2020 Contacts/Locations and Study Status
11 March 6, 2020 Contacts/Locations and Study Status
12 April 1, 2020 Study Status and Contacts/Locations
13 April 9, 2020 Contacts/Locations, Study Status, Study Identification, Eligibility and Outcome Measures
14 April 20, 2021 Contacts/Locations, Outcome Measures, Study Status, Eligibility and Study Description
15 May 18, 2021 Contacts/Locations and Study Status
16 June 15, 2021 Contacts/Locations and Study Status
17 July 13, 2021 Contacts/Locations and Study Status
18 August 12, 2021 Study Status and Contacts/Locations
19 September 11, 2021 Study Status and Contacts/Locations
20 October 6, 2021 Study Status and Contacts/Locations
21 November 3, 2021 Contacts/Locations and Study Status
22 December 1, 2021 Contacts/Locations and Study Status
23 December 20, 2021 Contacts/Locations, Study Description and Study Status
24 January 19, 2022 Study Status and Contacts/Locations
25 February 16, 2022 Study Status and Contacts/Locations
26 March 17, 2022 Contacts/Locations and Study Status
27 April 14, 2022 Contacts/Locations and Study Status
28 May 13, 2022 Study Status and Contacts/Locations
29 June 10, 2022 Study Status and Contacts/Locations
30 July 7, 2022 Study Status and Contacts/Locations
31 August 4, 2022 Study Status and Contacts/Locations
32 September 2, 2022 Study Status and Contacts/Locations
33 September 28, 2022 Contacts/Locations and Study Status
34 October 27, 2022 Study Status and Contacts/Locations
35 November 21, 2022 Contacts/Locations and Study Status
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Study NCT03785678
Submitted Date:  December 20, 2018 (v1)

Open or close this module Study Identification
Unique Protocol ID: ML40787
Brief Title: Tenecteplase in Stroke Patients Between 4 and 24 Hours (TIMELESS)
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)
Secondary IDs:
Open or close this module Study Status
Record Verification: December 2018
Overall Status: Not yet recruiting
Study Start: December 20, 2018
Primary Completion: September 30, 2020 [Anticipated]
Study Completion: September 30, 2022 [Anticipated]
First Submitted: December 19, 2018
First Submitted that
Met QC Criteria:
December 20, 2018
First Posted: December 24, 2018 [Actual]
Last Update Submitted that
Met QC Criteria:
December 20, 2018
Last Update Posted: December 24, 2018 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: Genentech, Inc.
Responsible Party: Sponsor
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary:

This study will evaluate the efficacy and safety of tenecteplase compared with placebo in patients with acute ischemic stroke (AIS). All patients will receive standard-of-care therapy according to American Heart Association / American Stroke Association clinical guidelines (2018). To determine eligibility for randomization, all patients will undergo multimodal CT or MRI at baseline. Only patients with a vessel occlusion (ICA or MCA) and penumbral tissue will be randomized.

The primary analysis is to compare the efficacy of tenecteplase versus placebo in all patients at Day 90.

Detailed Description:
Open or close this module Conditions
Conditions: THROMBOLYSIS
Keywords:
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 3
Interventional Study Model: Parallel Assignment
Number of Arms: 2
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation: Randomized
Enrollment: 456 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
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.
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.
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Ordinal modified Rankin scale (mRS) score
[ Time Frame: 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
[ Time Frame: 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 where planned thrombectomy was not performed
[ Time Frame: within 90 minutes from the randomization ]

The efficacy of Tenecteplase is evaluated in terms of proportion of patients where planned thrombectomy was not performed.
3. Proportion of patients with angiographic reperfusion
[ Time Frame: 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).
4. Median NIHSS score
[ Time Frame: Day 90 ]

The efficacy of Tenecteplase is evaluted in terms of Median NIHSS score at Day 90.
5. Proportion of patients with a Barthel Index (BI) score >=95
[ Time Frame: Day 90 ]

The efficacy of Tenecteplase is evaluated in terms of Proportion of patients with a BI score >=95 at Day 90.
6. Proportion of patients with a Glasgow Outcome Scale (GOS) of 1 at Day 90
[ Time Frame: Day 90 ]

The efficacy of Tenecteplase is evaluated in terms of proportion of patients with GOS of 1 at Day 90.
7. Proportion of patients with reperfusion at 24 hours post-treatment
[ Time Frame: Day 2 ]

The efficacy of Tenecteplase is evaluated in terms of proportion of patients with reperfusion at 24 hours post-treatment, defined as >90% reduction in Tmax>6s lesion volume
8. Proportion of patients with recanalization at 24 hours post-treatment
[ Time Frame: Day 2 ]

The efficacy of Tenecteplase is evaluated in terms of proportion of patients with recanalization at 24 hours post-treatment, defined as complete or partial recanalization on CT angiography (CTA)/magnetic resonance angiography (MRA).
9. Number of patients with symptomatic intracranial hemorrhage (sICH a)
[ Time Frame: Day 2 ]

The safety profile of Tenecteplase is evaluated in terms of number of patients with sICH within 36 hours
10. Incidence and severity of adverse events
[ Time Frame: From baseline up to day 90 ]

The safety profile of Tenecteplase is evaluated in terms of incidence and severity of adverse events.
11. Mortality rate at Day 30 and Day 90
[ Time Frame: Day 30 and Day 90 ]

The safety profile of Tenecteplase is evaluated in terms of mortality rate at Day 30 and Day 90
12. Proportion of patients with parenchymal hematoma type 2 (PH2) at 72 hours
[ Time Frame: Day 3 ]

The safety profile of Tenecteplase is evaluated in terms of proportion of patients with PH2 at 72 hours
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

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 MRA or CTA AND target mismatch profile on CT perfusion or MRI (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)
  • Pregnant
  • Intracranial neoplasm, 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)
  • Baseline platelet count <100,000/microL (results must be available prior to treatment)
  • 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) or life expectancy is 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
Open or close this module Contacts/Locations
Locations: United States, California
Adventist Health Glendale
Glendale, California, United States, 91206
UCSD Medical Center - La Jolla
La Jolla, California, United States, 92037
CHA Hollywood Presbyterian Medical Center
Los Angeles, California, United States, 90027
Kaiser Permanente Los Angeles
Los Angeles, California, United States, 90027
Adventist Healtl-Simi Valley
Simi Valley, California, United States, 93065
United States, Connecticut
Hartford Hospital
Hartford, Connecticut, United States, 06102
United States, Florida
Baptist Medical Center - Jacksonville
Jacksonville, Florida, United States, 32207-8202
University of Miami
Miami, Florida, United States, 33136
United States, Hawaii
The Queen's Medical Center
Honolulu, Hawaii, United States, 96813
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, Michigan
Henry Ford Hospital
Detroit, Michigan, United States, 48202
Ascension St. John Hospital
Detroit, Michigan, United States, 48236
United States, Missouri
Washington University
Saint Louis, Missouri, United States, 63128
United States, New Jersey
JFK Neuroscience Institute
Edison, New Jersey, United States, 08820
United States, North Carolina
Mission Hospitals Inc
Asheville, North Carolina, United States, 28803
United States, Oregon
Providence Saint Vincent's Medical Center
Portland, Oregon, United States, 97225
United States, Pennsylvania
Uni of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15213
United States, Rhode Island
Rhode Island Hospital
Providence, Rhode Island, United States, 02903
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
United States, Texas
Dell Seton Medical center at the University of Texas
Austin, Texas, United States, 78701
Baylor University Medical Center
Dallas, Texas, United States, 75226
Valley Baptist Medical Center
Harlingen, Texas, United States, 78550
University of Texas at Houston; Neurology
Houston, Texas, United States, 77030
United States, Utah
Intermountain Healthcare
Salt Lake City, Utah, United States, 84107
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
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