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ACT-GLOBAL IA Thrombolysis(ACT-REACT-004)Domain Within the ACT-GLOBAL Adaptive Platform Trial-NCT06352632 (ACT-REACT)

2026년 6월 29일 업데이트: Dr. Bijoy Menon, University of Calgary

A Multicentre,Prospective,Randomized,Open Label,Blinded-endpoint Trial for Reperfusion Enhancement After Completing Thrombectomy Using Intraarterial Thrombolysis(REACT-IA-Thrombolysis Domain)Embedded in A Multi-faCtorial,mulTi-arm, Multi-staGe,Randomised,gLOBal Adaptive pLatform Trial for Stroke(ACT-GLOBAL) NCT06352632

Study Design and Duration:

This domain will be conducted as part of ACT-GLOBAL platform trial and will have the nested domain name of REACT. It has a prospective, randomised, controlled, open-label, parallel group with blinded endpoint assessment (PROBE) design of up to 1,500 subjects with Acute Ischemic Stroke (AIS) who undergo EVT. Randomisation will be stratified by country/ region, and the IA thrombolytic agent (tenecteplase or alteplase). Minimal sufficient balance algorithm will operate within each stratum to preserve balance on key covariates while maintaining allocation randomness.

Participants will be followed for 90 days (or until death, if prior to 90 days). The end of the trial is defined as the date that all participants have completed their Day 90 assessment. Primary outcome data will be determined by simplified, structured method of assessment using the modified Rankin scale (mRS), conducted through centralized telephone interviews or online media performed by central trial personnel blinded to treatment assignment and received.

Domain Interventions:

The intervention group will receive a single dose of local intraarterial thrombolysis using either tenecteplase (at a dose of 0.0625mg/kg; maximum dose of 6.25mg) or alteplase (0.225 mg/kg; maximum dose, 20mg) at the end of EVT procedure plus standard of care while the control group will receive standard of care alone. The selection of the thrombolytic agent will be determined according to local availability. The dose of intraarterial thrombolysis will be increased if the above dose meets prespecified posterior probabilities at the first or second interims.

In all eligible patients:

  1. Local intra-arterial thrombolysis using either tenecteplase at a dose of 0.0625mg/kg "maximum dose of 6.25mg" or alteplase "0.225 mg/kg; maximum dose, 20mg*

  2. No intra-arterial thrombolysis.

    • The dose of IA thrombolysis may be doubled to 0.125 mg/kg tenecteplase or 0.45 mg/kg alteplase if this dose shows futility at pre-specified interims Randomization will be stratified by country/ region, the IA thrombolytic agent used (tenecteplase or alteplase). IA thrombolysis will be administered as a one-time treatment.

연구 개요

상태

아직 모집하지 않음

정황

개입 / 치료

상세 설명

This is a domain within the ACT-GLOBAL platform trial to compare IA thrombolysis use (Yes vs No) following the completion of endovascular thrombectomy procedures among subjects who did not receive IV thrombolysis.

The key arguments for the proposed trial are:

  • About 50% of patients treated with EVT are left with distal occlusions that cannot be reached with current devices. Even when reperfusion is considered complete, evidence suggests microthrombi persist in downstream cerebral circulation, contributing to poor outcomes.
  • Other approved acute stroke treatments such as intravenous thrombolysis or antithrombotics do not address incomplete reperfusion. Approximately half of stroke patients treated with EVT are not concurrently or pre-treated with IV thrombolysis.
  • Systemic antithrombotics used in conjunction with IV thrombolysis are unsafe or ineffective.
  • Prospective cohorts and randomized controlled trials (RCTs) suggest that targeted intraarterial thrombolysis offered directly to the affected arterial territory is a promising approach to enhance reperfusion when thrombectomy with mechanical devices is complete. Recent meta-analyses from small pilot studies suggest safety of this approach.
  • Recent RCTs showed mixed results but with overall potentially better clinical outcomes with intraarterial thrombolysis using either tenecteplase or alteplase.
  • A high quality, large, pragmatic, and globally representative confirmatory trial is needed to generate definitive evidence and inform clinical practice on the safety and benefit of IA thrombolysis.

Modern endovascular thrombectomy (EVT) offered using mechanical devices like stent-retrievers and aspiration catheters has revolutionized acute stroke therapy and improved outcomes. Still, a significant gap exists between EVT procedural success and clinical recovery in patients with large vessel occlusion stroke. Less than half of patients receiving EVT achieve functional independence (modified Rankin Scale "mRS" 0-2) despite medical care and rehabilitation. Moreover, ~15% of all EVT procedures fail with subsequent dismal outcomes. Incomplete reperfusion is a major reason that explains why many patients fail to recover fully after thrombectomy. This phenomenon occurs either because of clot fragments that lodge in distal arteries (micro-embolization), or because of in-situ thrombus formation in the micro-circulation. These occlusions are too distal for current devices to reach. However, they can be reached in a targeted manner by administering chemical thrombolysis directly into target areas through catheters lodged in large arteries.

While the incidence and consequences of macrocirculatory obstruction are well-described, microcirculatory obstruction (also called no-reflow) has not been extensively studied in stroke. Nonetheless, it has been reported in 25% of patients post successful EVT with associated higher odds of infarct growth, and poor functional outcomes including death. In an imaging sub study of the CHOICE phase II RCT (comparing local intraarterial "IA" alteplase vs placebo following successful thrombectomy), 58% of patients enrolled to the control arm demonstrated persistent hypoperfusion on MRI at 48 hours after successful EVT. This hypoperfusion was postulated to result from microcirculatory obstruction and was associated with poor outcomes.

Intravenous thrombolysis given prior to EVT may have some effect on lysing downstream thrombi once endovascular recanalization is achieved. However, around half of EVT-treated patients do not receive IV thrombolysis due to contraindications or presenting outside IV thrombolysis treatment window. In addition, the short half-life of IV thrombolytic agents (plasma elimination half-life of ~ 3.5 minutes for alteplase and ~20 minutes for tenecteplase) means that they may not have any effect on thrombi that persist after EVT is completed. In a study of 1303 patients from the German stroke registry, patients in whom the IV alteplase infusion was still ongoing at the end of EVT had higher odds of achieving excellent recovery compared to those who completed the infusion prior to EVT completion. Recent RCTs exploring antithrombotics agents to enhance reperfusion either showed harm (IV ASA ( acetylsalicylic acid) with or without IV heparin) or lack of benefit (IV tirofiban).

Targeted intra-arterial (IA) thrombolysis is a promising adjunct therapy that can be offered to enhance reperfusion immediately after EVT. Thrombolysis administered directly in the affected vascular bed maximizes the fibrinolytic effect on the local cerebral circulation while reducing systemic uptake and side effects. Different thrombolytic agents have been used for IA stroke therapy. However, meta-analyses suggest low quality evidence of available studies given their observational nature and restrictive selection criteria. In one meta-analysis of five observational studies (n=269 patients), there was a suggestion of better functional independence with intraarterial alteplase or urokinase over controls (OR: 1.34; 95% CI: 1.00 to 1.80) without increased risk of symptomatic hemorrhage or death. In the INFINITY registry conducted in 10 European centers, IA alteplase was associated with improved reperfusion in 50% of patients who achieved incomplete reperfusion after EVT. The phase II RCT (CHOICE, n=121 subjects) of IA alteplase after successful EVT at a dose equivalent to 25% of the maximum IV alteplase dosing showed the safety and efficacy of this approach. This trial was stopped prematurely due to placebo supply constraints. Still, it showed an absolute risk difference of 18.4% (95%CI 0.3%-36.4%; P=0.047) in excellent outcome (mRS 0-1) favouring IA alteplase, without increased risk of symptomatic intracranial haemorrhage. In an imaging sub study of the trial, 58% of patients enrolled to the control arm demonstrated persistent hypoperfusion on MRI despite angiographically successful EVT. These results need to be interpreted with caution however given small sample size and premature closure of study. A phase III RCT (PEARL, n=324 subjects) with a similar design and IA alteplase dosing as CHOICE was presented recently (unpublished) and showed improved mRS 0-1 in the treatment arm compared to controls with an absolute risk difference of 15% (95%CI 3.7%-26.3%; P=0.01).

Tenecteplase is a promising agent for IA thrombolysis. It has superior pharmacokinetic properties over alteplase including its longer half-life (~20 minutes), and greater fibrin specificity. Our large CIHR (Canadian Institute of Health Research) funded AcT (Alteplase compared to Tenecteplase) RCT (n=1600 subjects) demonstrated the non-inferiority and comparable safety of IV tenecteplase (0.25 mg/kg) vs. alteplase for all ischemic stroke patients eligible for IV thrombolysis. In 520 patients treated with EVT in AcT, there was a suggestion of better recanalization with tenecteplase and similar safety. The EXTENDIA-TNK trial showed superior recanalization and better outcomes among patients treated with IV tenecteplase vs those treated with IV alteplase. Therefore, tenecteplase is now the standard for IV thrombolysis in acute ischemic stroke. The current Canadian Best Practice guidelines recommend tenecteplase as an alternative to alteplase in all eligible stroke patients. Tenecteplase can be administered intraarterially and may help reperfuse the brain better than but as safe as IA alteplase. While two prior RCTs using IA tenecteplase in patients with anterior circulation (POST-TNK, n=540 subjects), and posterior circulation (ATTENTION, N=208 subjects) strokes following endovascular reperfusion showed neutral results, a recent phase III RCT of IA tenecteplase in anterior circulation stroke patients following endovascular reperfusion showed positive results. The ANGEL-TNK trial (n= 255 subjects) was recently presented and showed that patients treated with IA tenecteplase at a dose equivalent to 50% of the IV tenecteplase dose had better 90-day mRS 0-1 compared to controls (40.5% vs 26.4%, OR 1.4, 95%CI 1.1 to 2) without safety concerns.

While these results suggest a potential benefit of IA thrombolysis following thrombectomy, the heterogeneity of existing trials, their narrow geographic scope (conducted primarily in China or Spain), and the inconsistent benefit across key functional outcomes (e.g., improvement in mRS 0-1 but not mRS 0-2 or ordinal shift) underscore the necessity for a globally representative, large-scale, pragmatic confirmatory trial to provide definitive evidence and guide clinical practice.

Domain Rationale:

The key arguments for the proposed trial are:

  • About 50% of patients treated with EVT are left with distal occlusions that cannot be reached with current devices. Even when reperfusion is considered complete, evidence suggests microthrombi persist in downstream cerebral circulation, contributing to poor outcomes.
  • Other approved acute stroke treatments such as intravenous thrombolysis or antithrombotics do not address incomplete reperfusion. Approximately half of stroke patients treated with EVT are not concurrently or pre-treated with IV thrombolysis.
  • Systemic antithrombotics used in conjunction with IV thrombolysis are unsafe or ineffective.
  • Prospective cohorts and randomized controlled trials (RCTs) suggest that targeted intraarterial thrombolysis offered directly to the affected arterial territory is a promising approach to enhance reperfusion when thrombectomy with mechanical devices is complete. Recent meta-analyses suggest safety of this approach.
  • Recent RCTs showed mixed results but with overall potentially better clinical outcomes with intraarterial thrombolysis using either tenecteplase or alteplase. The combination of IV thrombolysis plus IA thrombolysis did not result in safety concerns.
  • A high quality, large, pragmatic, and globally representative confirmatory trial is needed to generate definitive evidence and inform clinical practice on the safety and benefit of IA thrombolysis.

DOMAIN AIMS AND OBJECTIVES

This domain aim is to efficiently, reliably, and simultaneously, determine the effectiveness of targeted intraarterial (IA) thrombolysis using either tenecteplase at a dose of 0.0625mg/kg (maximum dose of 6.25mg) or alteplase (0.225 mg/kg; maximum dose, 20mg) vs. no IA thrombolysis in all patients who undergo EVT. For participants allocated to the IA thrombolysis arm, the selection of thrombolytic agent (tenecteplase or alteplase) will be determined according to local availability.

This domain of the ACT-GLOBAL platform is designed in such a way that the accrued data could be used to design and then ask a future research question on IA thrombolysis in a pertinent subgroup of patients

연구 유형

중재적

등록 (추정된)

1500

단계

  • 3단계

연락처 및 위치

이 섹션에서는 연구를 수행하는 사람들의 연락처 정보와 이 연구가 수행되는 장소에 대한 정보를 제공합니다.

연구 연락처

연구 연락처 백업

연구 장소

  • 캐나다
    • Alberta
      • Calgary, Alberta, 캐나다, T2N2T9
        • University of Calgary- Foothills Medical Centre
        • 연락하다:
        • 연락하다:
        • 수석 연구원:
          • Mohammed Almekhlafi, MD
      • Edmonton, Alberta, 캐나다
        • University of Alberta
        • 수석 연구원:
          • Brian Buck, MD
        • 연락하다:
    • British Columbia
      • Kelowna, British Columbia, 캐나다
        • Kelowna Regional Hospital
        • 수석 연구원:
          • Aleksander Tkach, MD
      • New Westminster, British Columbia, 캐나다
        • Royal Columbian Hospital
        • 수석 연구원:
          • George Medvedev, MD
        • 연락하다:
          • Vishaya Naidoo
      • Vancouver, British Columbia, 캐나다
    • Manitoba
      • Winnipeg, Manitoba, 캐나다
        • University of Manitoba - Winnipeg Health Science Centre
        • 수석 연구원:
          • Nishita Singh, MD
        • 연락하다:
    • Ontario
      • Greater Sudbury, Ontario, 캐나다
        • Health Sciences North Horizon Sante-Nord
      • Ottawa, Ontario, 캐나다
        • Ottawa Civic Hospital
        • 수석 연구원:
          • Dariush Dowlatshahi, MD
        • 연락하다:
      • Toronto, Ontario, 캐나다
        • Sunnybrook Health Science Centre
        • 수석 연구원:
          • Richard Swartz, MD
        • 연락하다:
    • Quebec
    • Saskatchewan
      • Saskatoon, Saskatchewan, 캐나다
        • Royal University Hospital
  • 호주
    • Barangaroo
      • Sydney, Barangaroo, 호주, NSW 2000
        • The George Institute for Global Health
        • 수석 연구원:
          • Craig Anderson, MD
        • 연락하다:

참여기준

연구원은 적격성 기준이라는 특정 설명에 맞는 사람을 찾습니다. 이러한 기준의 몇 가지 예는 개인의 일반적인 건강 상태 또는 이전 치료입니다.

자격 기준

공부할 수 있는 나이

  • 성인
  • 고령자

건강한 자원 봉사자를 받아들입니다

아니

설명

Inclusion Criteria:

  1. Age ≥18 years
  2. Clinical diagnosis of stroke

Exclusion Criteria:

There are no platform level exclusion criteria.

공부 계획

이 섹션에서는 연구 설계 방법과 연구가 측정하는 내용을 포함하여 연구 계획에 대한 세부 정보를 제공합니다.

연구는 어떻게 설계됩니까?

디자인 세부사항

  • 주 목적: 치료
  • 할당: 무작위
  • 중재 모델: 병렬 할당
  • 마스킹: 하나의

무기와 개입

참가자 그룹 / 팔
개입 / 치료
활성 비교기: Local intra-arterial (IA) thrombolysis using either tenecteplase or alteplase
The intervention group will receive local intra-arterial (IA) thrombolysis using either tenecteplase at a dose of 0.0625mg/kg "maximum dose of 6.25mg" or alteplase "0.225 mg/kg; maximum dose, 20mg.
생물학적: Tenecteplase or Alteplase- depending upon availability at each treating centre
Intra-arterial thrombolysis after endovascular therapy
다른 이름들:
  • Thrombolytic (2 options)
  • tNKase, Metalyse,
  • tPA, Activase
위약 비교기: No IA thrombolysis
No intra-arterial thrombolysis.
다른: Control
No intra-arterial thrombolysis after endovascular therapy

연구는 무엇을 측정합니까?

주요 결과 측정

결과 측정
측정값 설명
기간
수정된 랜킨 척도(mRS)로 평가된 결과의 전체 분포에 걸쳐 분석된 기능적 의존성의 감소,
기간: 등록부터 90일차 평가까지 - 90일차 결과는 맹검 방식으로 평가됩니다.
수정된 랜킨 척도(mRS) - 0~1점은 증상이 있거나 없더라도 장애가 없는 양호한 결과를 나타내고, 2~5점은 장애(및 의존성) 수준이 증가함을 나타내며, 6점은 사망을 나타냅니다.
등록부터 90일차 평가까지 - 90일차 결과는 맹검 방식으로 평가됩니다.

2차 결과 측정

결과 측정
측정값 설명
기간
Rate of 90-day mortality
기간: From enrollment to the Day 90 assessment.
Date and cause of death are collected from randomization until End of Study.
From enrollment to the Day 90 assessment.

기타 결과 측정

결과 측정
측정값 설명
기간
The Proportion of participants with a Modified Rankin Scale (mRS) of 0-1 at Day 90.
기간: Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
Modified Rankin Scale (mRS) -which scores of 0 to 1 indicate a favourable outcome without or with symptoms but no disability, scores of 2 to 5 indicate increasing levels of disability (and dependency), and a score of 6 indicates death.
Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
The Proportion of participants with a Modified Rankin Scale (mRS) of 0-2 at Day 90.
기간: Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
Modified Rankin Scale (mRS) -which scores of 0 to 1 indicate a favourable outcome
Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
Rating the Health-related quality of life, as measured by the EQ-5D-5L at Day 90.
기간: Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
The EQ-5D-5L is a generic instrument for describing and valuing health. It is based on a descriptive system that defines health in terms of five dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has five response categories corresponding to: no problems, slight, moderate, severe and extreme problems. The version of the instrument selected for the trial is interviewer administered either in-person, or by telemedicine or by telephone. The respondents will also rate their overall health on the day of the interview on a 0-100 visual analogue scale (EQ-VAS).
Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
Safety Assessments of Serious Adverse Events (SAEs) from enrollment up to Day 4
기간: From enrollment ( randomization) to the Day 4
Serious Adverse events include the following events :results in death, life threatening,Requires inpatient hospitalization or prolongation of existing hospitalization,Results in persistent disability/incapacity,Is a congenital anomaly/birth defect, an important medical event that may not result in death, be life-threatening, or require hospitalization, but may jeopardize the participant and may require medical or surgical intervention to prevent an outcome listed in the SAE selection.
From enrollment ( randomization) to the Day 4
The proportion of patients with Symptomatic intracranial hemorrhage from enrolment up to Day 4
기간: From enrollment ( randomization) to the Day 4
Any new intracranial hemorrhage detected by brain imaging associated with neurological worsening or deterioration of symptoms.
From enrollment ( randomization) to the Day 4
The proportion of patients with large parenchymal hemorrhage (PH-2) from enrolment up to Day 4
기간: From enrollment ( randomization) to the Day 4
PH-2:( hemorrhage grading scale) homogeneous hyperdensity occupying over 30% of the infarct zone, with significant mass effect
From enrollment ( randomization) to the Day 4
The Ordinal shift of 7 levels of mRS at 90 days
기간: Done by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
Modified Rankin Scale (mRS) -which scores of 0 to 1 indicate a favourable outcome without or with symptoms but no disability, scores of 2 to 5 indicate increasing levels of disability (and dependency), and a score of 6 indicates death.
Done by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
The Proportion of participants achieving first pass (eTICI 2c or higher) reperfusion (when treated with EVT).
기간: Completed by the Central Core lab at 30 days after randomization
The thrombolysis in cerebral infarction (TICI) grading system as a tool for determining the response of thrombolytic therapy for ischemic stroke. In neurointerventional radiology it is commonly used for patients post endovascular revascularization.
Completed by the Central Core lab at 30 days after randomization
The Proportion of participants achieving successful recanalization (revised arterial occlusive lesion [rAOL] score of 2b-3) at first angiographic acquisition (when treated with EVT).
기간: Completed by the Central Core lab at 30 days after randomization
The thrombolysis in cerebral infarction (TICI) grading system as a tool for determining the response of thrombolytic therapy for ischemic stroke. In neurointerventional radiology it is commonly used for patients post endovascular revascularization.
Completed by the Central Core lab at 30 days after randomization
The Ambulatory status at discharge
기간: Completed at Day 4.
Assessing mobility of the patient at discharge
Completed at Day 4.
The Place of residence at 90 days
기간: Completed at the Day 90 assessment.
Assessing the patient's residence at the Day 90 follow up. ( example: home,rehabilitation, long term care, remains hospitalized)
Completed at the Day 90 assessment.
Imaging assessment of infarct size and edema volume
기간: Completed by the Central Core lab at 30 days after randomization
The total absolute infarct volume is the sum of infarct volumes calculated for each slice.
Completed by the Central Core lab at 30 days after randomization
Summative total length of hospital stay in the first 90-days after stroke onset
기간: Completed at the Day 90 assessment.
Calculating the total number of days the patient was hospitalized since their hospital admission.
Completed at the Day 90 assessment.

공동 작업자 및 조사자

여기에서 이 연구와 관련된 사람과 조직을 찾을 수 있습니다.

스폰서

University of Calgary

협력자

The George Institute for Global Health, Australia

수사관

  • 수석 연구원: Bijoy K Menon, MD, University Of Calgary
  • 수석 연구원: Craig Anderson, MD, The George Institute

연구 기록 날짜

이 날짜는 ClinicalTrials.gov에 대한 연구 기록 및 요약 결과 제출의 진행 상황을 추적합니다. 연구 기록 및 보고된 결과는 공개 웹사이트에 게시되기 전에 특정 품질 관리 기준을 충족하는지 확인하기 위해 국립 의학 도서관(NLM)에서 검토합니다.

연구 주요 날짜

연구 시작 (추정된)

2026년 6월 10일

기본 완료 (추정된)

2030년 12월 31일

연구 완료 (추정된)

2031년 3월 31일

연구 등록 날짜

최초 제출

2025년 9월 11일

QC 기준을 충족하는 최초 제출

2026년 6월 29일

처음 게시됨 (실제)

2026년 7월 7일

연구 기록 업데이트

마지막 업데이트 게시됨 (실제)

2026년 7월 7일

QC 기준을 충족하는 마지막 업데이트 제출

2026년 6월 29일

마지막으로 확인됨

2026년 6월 1일

추가 정보

이 연구와 관련된 용어

키워드

추가 관련 MeSH 약관

기타 연구 ID 번호

  • ACT REACT-004
  • ACT GLOBAL (기타 식별자: Clinical Trials.gov)

개별 참가자 데이터(IPD) 계획

개별 참가자 데이터(IPD)를 공유할 계획입니까?

아니요

IPD 계획 설명

Domain information and tabular trial results will be posted on the National Institutes of Health's website www.clinicaltrials.gov within one year of domain completion.

약물 및 장치 정보, 연구 문서

미국 FDA 규제 의약품 연구

아니

미국 FDA 규제 기기 제품 연구

아니

이 정보는 변경 없이 clinicaltrials.gov 웹사이트에서 직접 가져온 것입니다. 귀하의 연구 세부 정보를 변경, 제거 또는 업데이트하도록 요청하는 경우 register@clinicaltrials.gov. 문의하십시오. 변경 사항이 clinicaltrials.gov에 구현되는 즉시 저희 웹사이트에도 자동으로 업데이트됩니다. .

구독하다