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Acute Ischemic StrokePhase 2NCT03433235

Early Administration of Edoxaban After Acute Ischemic Stroke in Patients With Non-valvular Atrial Fibrillation

A Phase 2 study testing Edoxaban in people with Acute Ischemic Stroke, run by Jong Sung Kim at 1 site in South Korea.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

The investigators hypothesize that earlier initiation of edoxaban in AF-related stroke patients may significantly reduce the early recurrence of ischemic stroke, compared with conventional strategy of anticoagulation following 1-3-6-12 rule. Read more about this study

Who is it for?
Ages 20 years and older
Conditions the study is for
Acute Ischemic Stroke
What is being tested?
Edoxaban
Could I receive a placebo?
No, everyone receives an active treatment
How many people
68 participants
Where
1 siteSouth Korea
Study dates
19 Jun 2018to 2 Jul 2020
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 20 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Acute ischemic strokes (< 48 h from symptom onset) showing ischemic lesions confirmed by DWI, which are attributable to atrial fibrillation
  • Evidence of persistent or paroxysmal atrial fibrillation (already known or newly detected)
  • Age ≥20 y
  • Patients who provided informed consent

Who cannot join

  • Transient ischemic attack with no DWI lesions or severe ischemic strokes (NIHSS >16)
  • Significant hemorrhagic transformation (parenchymal hematoma type I or type II by the ECASS definition or those accompanying with worsening of an existing focal neurological deficit [NIHSS ≥4])10 on baseline MRI
  • Mechanical heart valve, rheumatic heart valve disease, or any other conditions requiring strong anticoagulation such as vitamin K antagonist or heparin treatment
  • Concomitant significant atherosclerotic stenosis (>50%) in the proximal arteries, which are possibly responsible for stroke lesions
  • Recent (<3 months) history of cerebral bleeding
  • Active internal bleeding or clinically significant bleeding
Show all 30Show fewer
  • Severe anemia (Hb <10 g/dL) or bleeding diathesis (platelet count <100,000/uL or PT-INR >1.7) (If there is no active bleeding sign, it is permitted to enroll Hb <9 g/dL , platelet count <70,000/uL)
  • Uncontrolled hypertension: persistent systolic pressure >180 mmHg or diastolic pressure >110 mmHg
  • Active, advanced medical diseases (liver, kidney, pulmonary disease or cancer) with a life expectancy <6 months
  • Renal impairment (CrCl <30 mL/min) or undergoing Hemodialysis (or Peritoneal Dialysis)
  • Treatment with a strong inducer of p-glycoprotein (carbamazepine, dexamethasone, doxorubicin, nefazodone, pentobarbital, phenobarbital, prazocin, rifampin, St.John's wort, tenofovir, tipranavir, trazodone, vinblastine)
  • Contraindication to MRI
  • Pregnancy, breast-feeding or having a plan to be pregnant
  • Participation in the other investigational drug trials simultaneously or within 3 months before the first administration of the study medication. Observational studies without an intervention (eg study medication) are allowed.
  • Any clinical conditions (eg abnormal lab tests) unsuitable for undergoing clinical trials at the discretion of the clinical investigators
  • Known hypersensitivity to the study drug (edoxaban), its ingredients, or formulation excipients
  • Patient with liver disease related to coagulation disorder and clinically significant bleeding risk
  • Severe Liver disease
  • Patient who has increase risk of bleeding due to the following disease
  • recent gastrointestinal ulcer history
  • carcinoma increased risk of bleeding
  • recent brain or spinal injury
  • recent brain, spinal or optical surgery histroy
  • esophageal varix
  • arteriovenous malformations
  • vascular aneurysms (over 3.5cm)
  • intra spinal or cerebral vascular disorder
  • Patient with other anticoagulants
  • intermitant or severe mitral stenosis
  • a pulmonary embolism patient who is hemodynamic unstabled or required thrombolytic therpy or pulmonary emnolectomy

Trial locations and contacts

1 site in 1 country.

South Korea1 site

  • Asan Medical Center

    Seoul

Other trials in South Korea

About this study

Official title: Early Administration of Edoxaban After Acute Ischemic Stroke in Patients With Non-valvular Atrial Fibrillation: a Randomized, Multi-center, Parallel-group Trial (PILOT)

The investigators hypothesize that earlier initiation of edoxaban in AF-related stroke patients may significantly reduce the early recurrence of ischemic stroke, compared with conventional strategy of anticoagulation following 1-3-6-12 rule. To expedite the verification of the hypothesis, the investigators are planning to use diffusion weighted imaging (DWI), which has been reported to be a surrogate to predict both short-term and long-term prognosis after stroke, to detect the recurrent ischemic events. Because data on the early anticoagulation in patients with AF-related stroke are limited, the investigators decided to perform a pilot study before establishing an appropriate clinical trial protocol. This study will help estimate the efficacy and safety of early administration of edoxaban, and determine the sample size of a following clinical trial. To ensure the safety in this pilot exploration, the investigators will not include patients with severe ischemic strokes, who are often prone to experience hemorrhagic transformation in the acute post-stroke period.

Read the detailed description

In patients with ischemic stroke and atrial fibrillation (AF), the risk of stroke recurrence is high, especially shortly after the event. Because AF-related strokes are usually larger in their size and more fatal than other types of ischemic stroke, it is important to prevent recurrent cardioembolic strokes with adequate secondary prevention. However, as damaged brain tissues and vessels are prone to bleed, early anticoagulation may be harmful.

For this reason, urgent anticoagulation has not been recommended in stroke patients with AF, and the appropriate time point to start anticoagulation remains controversial. Guideline recommends 1-3-6-12 rule* in initiating anticoagulation. However, this rule is not derived from a scientifically proven study results. Furthermore, although the risk of intracranial hemorrhage may be reduced to some extent with this strategy, the risk of early recurrence of embolic stroke may outweigh the potential benefit of delayed anticoagulation.

Edoxaban, which selectively blocks factor Xa, has a lower risk of hemorrhage, but with a similar efficacy in preventing ischemic events in patients with AF compared with warfarin. Even compared with the other factor Xa inhibitors, it is considered to have a lower risk of bleeding. Therefore, edoxaban may be safely given in the early phase in patients with stroke associated with AF, while not significantly increasing the risk of hemorrhages.

Being tested
Edoxaban
Medical subject headings
Ischemic Stroke

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EdoxabanDrug

    Also called Lixiana

    1-3-6-12 rule*

    Anticoagulation in patients with acute ischemic stroke and atrial fibrillation can be initiated from the following days after stroke event.

    After 1 day: transient ischemic attacks

    After 3 days: mild ischemic strokes (NIHSS <8)

    After 6 days: moderate ischemic strokes (NIHSS 8-16)

    After 12 days: severe ischemic strokes (NIHSS >16)

    • NIHSS: National Institute of Health Stroke Scales
Study groups in NCT03433235
Study groupRoleWhat they receive
Early edoxaban initiation groupExperimentalLow dose of edoxaban (15 or 30 mg) once daily from Day 2, then standard dose of edoxaban (30 or 60 mg) according to '3-6' rule.
Receives: Drug: Edoxaban
Conventional edoxaban initiation groupActive comparatorNo antithrombotic treatment† -- then standard dose of edoxaban (30 or 60 mg) according to '3-6' rule.
Receives: Drug: Edoxaban

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. recurrent ischemic strokes

    The incidence rate of symptomatic or asymptomatic recurrent ischemic strokes on DWI

    Measured: at Day 10-14

Secondary outcomes (5)

  1. Recurrent ischemic lesions

    The incidence rate of recurrent ischemic lesions with significant clinical worsening (≥NIHSS 4)

    The National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.

    Measured: until Day 10-14

  2. Clinical neurological deterioration

    The rate of clinical neurological deterioration, rapid worsening of an existing focal neurological deficit (≥ 24 hours) that is clinically judged by the investigator not to be attributable to non-ischemic etiology (≥NIHSS 2)

    The National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.

    Measured: until Day 10-14

  3. recanalization (full or partial) of occluded vessels

    The rate of recanalization (full or partial) of occluded vessels on follow-up intracranial TOF

    Measured: at Day 10-14

  4. intracranial hemorrhages

    The incidence rate of intracranial hemorrhages on follow-up gradient echo (GRE)

    Measured: at Day 10-14

  5. Functional status

    Functional status (modified Rankin Scale [mRS])

    The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability.

    The scale runs from 0-6, running from perfect health without symptoms to death. 0 - No symptoms.

    1. - No significant disability. Able to carry out all usual activities, despite some symptoms.
    2. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
    3. - Moderate disability. Requires some help, but able to walk unassisted.
    4. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
    5. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
    6. - Dead.

    Measured: at 3 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Feb 2018
  2. Study start19 Jun 2018
  3. Primary completion14 Apr 2020
  4. Study completion2 Jul 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
68 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03433235
Sponsor's protocol ID
AMC 2018-0033
Status last verified
Dec 2020
First submitted
8 Feb 2018
Last updated
11 Dec 2020
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Lin HJ, Wolf PA, Kelly-Hayes M, Beiser AS, Kase CS, Benjamin EJ, D'Agostino RB. Stroke severity in atrial fibrillation. The Framingham Study. Stroke. 1996 Oct;27(10):1760-4. doi: 10.1161/01.str.27.10.1760.

    PubMed 8841325

  • Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, Khatri P, McMullan PW Jr, Qureshi AI, Rosenfield K, Scott PA, Summers DR, Wang DZ, Wintermark M, Yonas H; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013 Mar;44(3):870-947. doi: 10.1161/STR.0b013e318284056a. Epub 2013 Jan 31.

    PubMed 23370205

  • Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J. 2013 Jul;34(27):2094-106. doi: 10.1093/eurheartj/eht134. Epub 2013 Apr 26.

    PubMed 23625209

  • Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P; ESC Scientific Document Group. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: Executive summary. Eur Heart J. 2017 Jul 14;38(27):2137-2149. doi: 10.1093/eurheartj/ehw058.

    PubMed 27282612

  • Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19.

    PubMed 24251359

  • Schulman S. New oral anticoagulant agents - general features and outcomes in subsets of patients. Thromb Haemost. 2014 Apr 1;111(4):575-82. doi: 10.1160/TH13-09-0803. Epub 2014 Jan 23.

    PubMed 24452881

  • Kang DW, Han MK, Kim HJ, Sohn H, Kim BJ, Kwon SU, Kim JS, Warach S. Silent new ischemic lesions after index stroke and the risk of future clinical recurrent stroke. Neurology. 2016 Jan 19;86(3):277-85. doi: 10.1212/WNL.0000000000002289. Epub 2015 Dec 18.

    PubMed 26683639

  • Lee EJ, Kang DW, Warach S. Silent New Brain Lesions: Innocent Bystander or Guilty Party? J Stroke. 2016 Jan;18(1):38-49. doi: 10.5853/jos.2015.01410. Epub 2015 Oct 15.

    PubMed 26467195

  • Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998 Oct 17;352(9136):1245-51. doi: 10.1016/s0140-6736(98)08020-9.

    PubMed 9788453

  • Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.

    PubMed 15842354

  • Duchin K, Duggal A, Atiee GJ, Kidokoro M, Takatani T, Shipitofsky NL, He L, Zhang G, Kakkar T. An Open-Label Crossover Study of the Pharmacokinetics of the 60-mg Edoxaban Tablet Crushed and Administered Either by a Nasogastric Tube or in Apple Puree in Healthy Adults. Clin Pharmacokinet. 2018 Feb;57(2):221-228. doi: 10.1007/s40262-017-0554-0.

    PubMed 28512699

  • Seiffge DJ, Traenka C, Polymeris A, Hert L, Peters N, Lyrer P, Engelter ST, Bonati LH, De Marchis GM. Early start of DOAC after ischemic stroke: Risk of intracranial hemorrhage and recurrent events. Neurology. 2016 Nov 1;87(18):1856-1862. doi: 10.1212/WNL.0000000000003283. Epub 2016 Sep 30.

    PubMed 27694266

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Edoxaban in people with Acute Ischemic Stroke, run by Jong Sung Kim at 1 site in South Korea.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

recurrent ischemic strokes (time frame: at Day 10-14). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03433235, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Dec 2020.

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