Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation (START)
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| ClinicalTrials.gov Identifier: NCT03021928 |
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Recruitment Status :
Recruiting
First Posted : January 16, 2017
Last Update Posted : November 4, 2022
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Title:
Optimal Delay Time to Initiate Anticoagulation after Ischemic Stroke in Atrial Fibrillation (START): a pragmatic, adaptive randomized clinical trial.
Primary Objective:
• To determine the optimal time to initiate anticoagulation with a Non-Vitamin K Oral Anticoagulant (NOAC) after ischemic stroke in patients with non-valvular atrial fibrillation.
Secondary Objectives:
- To compare the rates of primary adverse outcomes in a per protocol analysis
- To compare 30 day clinical outcomes by the modified Rankin scale among the time-to-treatment groups
- To compare 30 day clinical outcomes by the PROMIS-10 scale among the time-to-treatment groups.
- To compare 90 day clinical outcomes by the modified Rankin scale among the time-to-treatment groups
- To explore the optimal timing in subgroups of age, sex, outcome category, and NOAC choice
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Stroke | Other: Time-To-Treatment Randomization | Phase 3 |
Long-term oral anticoagulation is standard for secondary stroke prevention in patients with atrial fibrillation (AFib). However, there is limited data and no consensus on the timing of when to initiate anticoagulation therapy, and concern that starting too soon risks symptomatic hemorrhagic transformation. These data are derived almost exclusively from heparins and Vitamin K antagonists (e.g.,warfarin). Now that NOACs have become the mainstay of stroke prophylaxis in AFib and have more rapid and consistent anticoagulation and fewer strokes (hemorrhagic especially), the question of optimal timing of NOAC initiation is of increasing importance.
The primary aim is to determine the time-to-treatment interval with the lowest associated risk for adverse events in the context of anticoagulation therapy with NOACs for acute stroke patients with non-valvular AFib. The question will be investigated with a prospective, adaptive, randomized, controlled "dose-exploration" trial with the time to treatment with NOAC therapy treated as the incremental "dose".
An adaptive, pragmatic trial will be performed that will not deviate from the treating physicians' usual practice except for randomizing the time to start the NOAC. Data collection will be limited to those fields necessary for the planned primary and secondary analyses.
The composite primary outcome event will be any of the following within 30 days of the index stroke: Ischemic Events (symptomatic ischemic stroke or systemic embolism), Hemorrhagic Events (symptomatic hemorrhagic transformation of index ischemic stroke, other symptomatic intracranial hemorrhage, or major extracranial hemorrhage), or all-cause mortality.
Four time-to-treatment intervals, i.e. study arms, between 2 and 14 days will be investigated: 60 hours, 132 hours, 228 hours, and 324 hours. An innovative adaptive design will be used which includes response adaptive randomization and modeling of ischemic and hemorrhagic outcome events. The ischemic and hemorrhagic events within the composite primary endpoint are modeled separately using their known monotonic property that the risk of an event increases (ischemic) or decreases (hemorrhage) as the time-to-treatment interval lengthens. Interim analyses will occur after every 100 subjects are randomized, where the primary outcome will be analyzed and new randomization probabilities will be calculated to favor the arms that have a better risk-profile.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 200 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Single (Outcomes Assessor) |
| Primary Purpose: | Prevention |
| Official Title: | Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation |
| Actual Study Start Date : | June 14, 2017 |
| Estimated Primary Completion Date : | August 2023 |
| Estimated Study Completion Date : | December 2023 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: 96 hours
Time to delay the initiation of anticoagulation is determined at randomization. The Time-To-Treatment Randomization of 96 hours correlates to starting treatment on Day 4, 132 hours starts on Day 6, 228 hours starts on Day 10, and 324 hours starts Day 14.
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Other: Time-To-Treatment Randomization
The time after symptom onset to initiate treatment will be randomized to one of four possible treatment arms: 60 hours, 132 hours, 228 hours, or 324 hours (+/- 12 hours each). |
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Experimental: 132 hours
Time to delay the initiation of anticoagulation is determined at randomization. The Time-To-Treatment Randomization of 96 hours correlates to starting treatment on Day 4, 132 hours starts on Day 6, 228 hours starts on Day 10, and 324 hours starts Day 14.
|
Other: Time-To-Treatment Randomization
The time after symptom onset to initiate treatment will be randomized to one of four possible treatment arms: 60 hours, 132 hours, 228 hours, or 324 hours (+/- 12 hours each). |
|
Experimental: 228 hours
Time to delay the initiation of anticoagulation is determined at randomization. The Time-To-Treatment Randomization of 96 hours correlates to starting treatment on Day 4, 132 hours starts on Day 6, 228 hours starts on Day 10, and 324 hours starts Day 14.
|
Other: Time-To-Treatment Randomization
The time after symptom onset to initiate treatment will be randomized to one of four possible treatment arms: 60 hours, 132 hours, 228 hours, or 324 hours (+/- 12 hours each). |
|
Experimental: 324 hours
Time to delay the initiation of anticoagulation is determined at randomization. The Time-To-Treatment Randomization of 96 hours correlates to starting treatment on Day 4, 132 hours starts on Day 6, 228 hours starts on Day 10, and 324 hours starts Day 14.
|
Other: Time-To-Treatment Randomization
The time after symptom onset to initiate treatment will be randomized to one of four possible treatment arms: 60 hours, 132 hours, 228 hours, or 324 hours (+/- 12 hours each). |
- Recurrent IschemicEvent [ Time Frame: 30 days ]Any symptomatic ischemic stroke or systemic embolism as evidenced by either CT or MRI
- Hemorrhagic Event [ Time Frame: 30 days ]Any symptomatic hemorrhagic transformation of index ischemic stroke, other symptomatic intracranial hemorrhage, or major extracranial hemorrhage as evidenced by CT or MRI
- Modified Rankin Scale [ Time Frame: 30 days ]A modified Rankin scale (mRS) assessment will be performed by a qualified staff member.
- PROMIS-10 Scale [ Time Frame: 30 days ]Patient-Reported Outcomes Measurement Information System-10 scale will be performed by a qualified staff member.
- Modified Rankin Scale [ Time Frame: 90 days ]A modified Rankin scale (mRS) assessment will be performed by a qualified staff member.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | Child, Adult, Older Adult |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- New disabling neurological deficit attributable to new ischemic stroke.
- Minimum lesion diameter of 1.5cm on qualifying imaging. If lesion not visible on imaging, NIHSS must be greater than 4.
- Non-valvular atrial fibrillation (paroxysmal, persistent, or permanent).
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Not currently anticoagulated and/or will not be anticoagulated prior to starting their NOAC at the randomized time of initiation (except for DVT prophylaxis).
Note: Patients who had been taking an anticoagulant prior to their qualifying index event (for any reason) are eligible for START, assuming the drug is no longer having a therapeutic effect in the patient's system by 48 hours from stroke onset.
- Treating physician plans to anticoagulate with a FDA-approved novel oral anticoagulant (NOAC): apixaban, dabigatran, edoxaban, or rivaroxaban, or other FDA-approved NOAC.
- Qualifying brain CT or MRI scan < 48hr from stroke onset (time last known well). If patient has been treated with thrombolytic or endovascular therapy for this stroke, then the qualifying scan is that which is performed after therapy to rule out clinically significant hemorrhagic transformation.
- Ability to randomize within 60 hours of symptom onset.
Exclusion Criteria:
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Any clinical or imaging evidence of spontaneous intracranial hemorrhage in the previous 6 months.
Note: Patients with hemorrhagic transformation of current or previous ischemic stroke may be included per Investigator's judgment. Sporadic microbleeds may be included per Investigator's judgment. As a general recommendation, a cerebral microbleed is considered to be ≤ 5mm, but sometimes up to 10mm, in greatest diameter on gradient recalled echo (GRE), or T2*, MRI sequences. Any blood visualized on a CT will be classified as a macrobleed.
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Infarct volume (estimated) is greater than 50% of middle cerebral artery territory on qualifying scan. If the full extent of the lesion is not visible, any patient with a NIHSS > 23 must be excluded.
Note: The lesion does not need to be restricted to the mCA, but if the lesion volume is estimated to be greater than half of the mCA territory, the patient should be excluded.
Note: In non-EVT patients, any NIHSS following the index stroke may be used to qualify the patient for START. For example, a patient that presents with a NIHSS of 10 who then receives tPA and improves to a NIHSS of 2 is still eligible for START. For patients whom had endovascular therapy, the qualifying NIHSS assessment is that which is obtained with their qualifying scan following therapy.
- Anticipated need for major surgery over the next 30 days that would require delay, discontinuation, or extended suspension of anticoagulant of more than 5 days.
- Symptomatic edema expected from size and location of ischemic stroke.
- Decreased level of consciousness present or expected.
- Life expectancy less than 90 days.
- Follow-up in person or by telephone for 90 days is not feasible.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03021928
| Contact: Patrick Lawrence, BS | 512-495-5925 | patrick.lawrence@austin.utexas.edu |
| United States, Texas | |
| Dell Seton Medical Center at The University of Texas | Recruiting |
| Austin, Texas, United States, 78701 | |
| Contact: Patrick Lawrence, BS 512-495-5925 patrick.lawrence@austin.utexas.edu | |
| Principal Investigator: Steven Warach, MD, PhD | |
| Principal Investigator: Truman J Milling, MD | |
| Sub-Investigator: Ming Ding, MD, PhD | |
| Sub-Investigator: Jefferson Miley, MD | |
| Seton Medical Center Austin | Recruiting |
| Austin, Texas, United States, 78705 | |
| Contact: Patrick Lawrence, BS 512-495-5925 patrick.lawrence@austin.utexas.edu | |
| Principal Investigator: Steven Warach, MD, PhD | |
| Principal Investigator: Truman J Milling, MD | |
| Sub-Investigator: Ming Ding, MD, PhD | |
| Sub-Investigator: Jefferson Miley, MD | |
| St. David's Medical Center | Not yet recruiting |
| Austin, Texas, United States, 78705 | |
| Contact: Krishna Saini, BS 512-544-8070 Krishna.Saini@stdavids.com | |
| Contact: Matt Cowperthwaite, PhD 5125448059 Matthew.Cowperthwaite@stdavids.com | |
| Principal Investigator: Angel Pulido, MD | |
| CHI St. Joseph Health Regional Hospital | Recruiting |
| Bryan, Texas, United States, 77802 | |
| Contact: Debbie Lewis, RN 979-776-5364 DLewis@st-joseph.org | |
| Principal Investigator: Bradley White, MD | |
| Texas Health Presbyterian Hospital | Recruiting |
| Dallas, Texas, United States, 75231 | |
| Contact: Deborah Tran, MS, RN deborahstabell@texashealth.org | |
| Principal Investigator: Samir Shah, MD | |
| Parkland Memorial Hospital | Recruiting |
| Dallas, Texas, United States, 75235 | |
| Contact: Cheyenne Marcelus, MS 214-648-8181 cheyenne.marcelus@UTSouthwestern.edu | |
| Principal Investigator: Ty Shang, MD | |
| Baylor University Medical Center | Recruiting |
| Dallas, Texas, United States, 75246 | |
| Contact: Jon Thammavong Jon.Thammavong@BSWHealth.org | |
| Principal Investigator: Rashedul Hasan, MD | |
| UT Southwestern William P. Clements Hospital | Recruiting |
| Dallas, Texas, United States, 75390 | |
| Contact: Cheyenne Marcelus, MS cheyenne.marcelus@UTSouthwestern.edu | |
| Principal Investigator: Ty Shang, MD | |
| UT Southwestern Zale Lipshy University Hospital | Recruiting |
| Dallas, Texas, United States, 75390 | |
| Contact: Cheyenne Marcelus, MS 214-648-8181 cheyenne.marcelus@UTSouthwestern.edu | |
| Principal Investigator: Ty Shang, MD | |
| Texas Tech University Health Science Center - El Paso University Medical Center | Recruiting |
| El Paso, Texas, United States, 79905 | |
| Contact: Israel Alba, BS 915-215-4616 israel.alba@ttuhsc.edu | |
| Principal Investigator: Salvador Cruz-Flores, MD | |
| Texas Health Harris Methodist Hospital | Recruiting |
| Fort Worth, Texas, United States, 76104 | |
| Contact: James Ryan, MSN JamesRyan@texashealth.org | |
| Principal Investigator: Clauida Perez, MD | |
| The University of Texas Health Science Center at Houston | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Alyssa Trevino, BA Alyssa.D.Trevino@uth.tmc.edu | |
| Principal Investigator: Nour Abdelhamid, MD | |
| Seton Medical Center Hays | Recruiting |
| Kyle, Texas, United States, 78640 | |
| Contact: Patrick Lawrence, BS 512-495-5925 patrick.lawrence@austin.utexas.edu | |
| Principal Investigator: Steven Warach, MD, PhD | |
| Principal Investigator: Truman J Milling, MD | |
| Sub-Investigator: Ming Ding, MD, PhD | |
| Sub-Investigator: Jefferson Miley, MD | |
| Seton Medical Center Williamson | Recruiting |
| Round Rock, Texas, United States, 78665 | |
| Contact: Patrick Lawrence, BS 512-495-5925 patrick.lawrence@austin.utexas.edu | |
| Principal Investigator: Steven Warach, MD, PhD | |
| Principal Investigator: Truman J Milling, MD | |
| Sub-Investigator: Ming Ding, MD, PhD | |
| Sub-Investigator: Jefferson Miley, MD | |
| The University of Texas Health Science Center at San Antonio | Recruiting |
| San Antonio, Texas, United States, 78229 | |
| Contact: Floyd Jones, BS JONESFA@uthscsa.edu | |
| Principal Investigator: Santiago Palacios, MD | |
| Principal Investigator: | Steven Warach, MD, PhD | Dell Medical School at The University of Texas at Austin | |
| Principal Investigator: | Truman J Milling, MD | Dell Medical School at The University of Texas at Austin | |
| Study Chair: | Patrick Lawrence, BS | Dell Medical School at The University of Texas at Austin |
Publications:
| Responsible Party: | Steven Warach, MD, PhD, Director; Professor, University of Texas at Austin |
| ClinicalTrials.gov Identifier: | NCT03021928 |
| Other Study ID Numbers: |
2017-09-0035 |
| First Posted: | January 16, 2017 Key Record Dates |
| Last Update Posted: | November 4, 2022 |
| Last Verified: | November 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | Yes |
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Stroke Atrial Fibrillation Anticoagulation NOAC |
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Stroke Ischemic Stroke Atrial Fibrillation Cerebrovascular Disorders Brain Diseases Central Nervous System Diseases |
Nervous System Diseases Vascular Diseases Cardiovascular Diseases Arrhythmias, Cardiac Heart Diseases Pathologic Processes |