ACUTE INTERVENTIONAL TRIAL SUMMARIES

• StrokeNet Thrombectomy Endovascular Platform (STEP)

  
  
  

  Title: StrokeNet Thrombectomy Endovascular Platform (STEP) Master Protocol
  Study description:	STEP is a Randomized, Multifactorial, Adaptive Platform trial that seeks to optimize the care of patients with acute ischemic stroke (AIS) due to large or medium vessel occlusions (LVOs and MVOs). This Master Protocol describes trial procedures, data collection, data monitoring, follow-up visits, and safety procedures that will be employed in all Domain-Specific Appendices. STEP is a registry-based trial; it uses data from existing registries to record information for a subset of the trial Case Report Form (CRF). Additional registry data from non-randomized STEP patients may be used for trial screening, planning, and generalizability assessment purposes.
  Objectives:	To determine the optimal strategy for treatment of patients with AIS due to LVOs or MVOs
  Endpoints:	In the Master Protocol we define the general outcomes of interest. Individual domains may define additional endpoints of interest. Clinical Efficacy Measures 90 (+/-15)-day global disability assessed with the modified Rankin Scale Global disability assessed with the modified Rankin Scale at discharge Neurologic deficit [NIH Stroke Scale (NIHSS)], at 24 (+/-12) hours Safety Endpoint Measures The following safety endpoints will be analyzed in both EVT and MM patients: Symptomatic intracranial hemorrhage within 36 hours of randomization Any radiologic intracranial hemorrhage within 36 hours of randomization Mortality by 90 (+/-15) days Serious adverse events within 90 (+/-15) days Additional trial-specific protocol endpoints may be defined in individual Domain-Specific Appendices and will only be collected in individuals enrolled in those particular domains.
  Study population:	Patients with acute ischemic stroke due to large or medium vessel occlusion who are potentially amenable to endovascular therapy.
  Description of Sites/Facilities:	Up to 50 Comprehensive Stroke Centers within the United States and Canada
  Description of Study Interventions:	Defined in Domain-specific Appendices
  Participant duration:	90 (±) 15 Days
  ClinicalTrials.gov number:	NCT06289985

• SISTER (Strategy for Improving Stroke Treatment Response)

   

  Trial Summary:  
  SISTER is a phase-2, prospective, randomized, placebo-controlled, blinded, dose finding trial that aims to determine the safety and preliminary efficacy of TS23. TS23 is a monoclonal antibody against the alpha-2 antiplasmin (α2-AP), in acute ischemic stroke. The study will be conducted at up to 50 U.S. sites and enroll a total of 300 adults (>18 years) with acute ischemic stroke who have a baseline NIHSS >6 and are able to receive study drug within 4.5-24 hours after stroke onset (or last known well) who have evidence of core-penumbra mismatch on baseline perfusion imaging and are not planned for endovascular intervention or standard of care intravenous (IV) thrombolysis.

  Trial Design and Outcomes: 
  The study will have four intervention arms of TS23 with doses of 3 mg/kg, 5 mg/kg, 7 mg/kg and 10 mg/kg compared to placebo. TS23/placebo will be administered in one dose intravenously over approximately 15 minutes. The subjects will be monitored, in-hospital, for 3 days or discharge, whichever is first. They will have study visits at 30 days and 90 days post study drug administration. The subjects will have PK specimens obtained prior to study drug administration, 3 hours, 30 hours and 90 days post study drug administration. Anti-drug antibodies will be obtained prior to study drug administration and at 90-day follow-up. Research related fibrinogen levels will also be drawn, processed and resulted locally.

  The study will be monitoring for the following safety outcomes:

  • Incidence of symptomatic ICH within 30 hours of study drug administration
  • Incidence of non-ICH major or clinically relevant non-major bleeding withing 30 days of study drug administration
  • Non-bleeding, serious adverse events within 90 days of study drug administration
  • Incidence of stroke-related and all-cause deaths within 90 days
  • Plasma fibrinogen levels at 3 hours after completion of study drug administration
    
    

  Objectives: To identify a dose of TS23 that is safe and more efficacious than placebo for the treatment of patients from 4.5 – 24 hours of ischemic stroke onset, or last know well, who have evidence of core-penumbra mismatch on perfusion imaging and are not a candidate for standard of care reperfusion therapies.
  

  
  Primary Endpoints:

  1. Safety: Any intracranial hemorrhage (ICH) visualized on the CT scan at 30 hours (+/- 6) after study drug administration.
  2. Efficacy: NIHSS score at 30 hours (+/- 6) after study drug administration (adjusted for the baseline in analysis)
     
     

  Secondary Endpoints:

  1. Biomarker Efficacy

  
  

  Analysis: This study is a Phase IIa, Bayesian, adaptive, dose-finding trial. This study was designed and all simulations were performed using the Fixed and Adaptive Clinical Trial Simulator FACTS™ v6.4 Core Design software developed by Berry Consultants. The Primary Analysis will be Bayesian. We will test whether the best dose of TS23 has at least 25% Utility (Promising Zone). The trial is a success if the best dose has utility of 0.25 or higher with at least 80% probability. Such a utility can be achieved through various combinations of 24-hour NIHSS improvement and ICH rate.

  Sponsors:

  • The National Institute of Neurological Disorders and Stroke (NINDS)
  • Translational Sciences, Inc.
    
    

  Lead Investigator:
  

  • Eva Mistry MBBS, MSCI – The University of Cincinnati, College of Medicine Department of Neurology

  
  Other Collaborators:

  • PI Team – can be included individually for research team:
    • Eva Mistry MBBS, MSCI
    • Pooja Khatri MD, MSc
    • Guy Reed MD, MS
    • Jordan Elm PhD
  • Project Managers:
    • PRIME – Sarah Bailey MS
    • NCC – Pam Plummer MSN, RN, CCRC
  • Additional Collaborators
    • NIH StrokeNet National Data Management Center at Medical University of South Carolina
    • NIH StrokeNet National Coordinating Center at the University of Cincinnati
    • University of Cincinnati Imaging Management Center
    • University of Arizona
    • University of California, San Francisco

   

• RHAPSODY-2: 3K3A-APC following administration of thrombolysis, mechanical thrombectomy, or both, in subjects with moderate to severe acute ischemic stroke

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  Trial Summary:

  

  This is a multicenter, randomized, placebo-controlled, double-blind, Phase 3 study, performed in coordination with StrokeNet to evaluate the efficacy and safety of 3K3A‑APC following administration of thrombolysis, mechanical thrombectomy, or both, in subjects with moderate to severe acute ischemic stroke. Subjects will be considered for the study if they are eligible for thrombolysis administration, mechanical thrombectomy, or both, for acute ischemic stroke with National Institutes of Health Stroke Scale (NIHSS) score ≥5.

  The study will be conducted at approximately 60 United States (US) sites and approximately 40 non-US sites.

  Trial Design and Outcomes: 

  The study will be conducted in 2 phases: the lead-in dose-finding phase and the definitive phase.  During the lead-in dose-finding phase, a maximum of 360 subjects will be randomized to 3K3A-APC (10, 15, or 30 mg) or placebo using a Bayesian adaptive approach.  Randomized subjects will receive 3K3A-APC or placebo (control) every 12 hours for 5 doses (approximately 3 days) or until discharge from the hospital (whichever occurs first).  Subjects will be monitored through Day 7/Discharge and on Days 30, 60 (phone/virtual), and 90.  The lead-in phase will transition to 1 selected 3K3A‑APC dose and recruitment will continue when a single dose proves superior to control, as measured by the proportion of intracerebral bleeding or death. If more than 1 dose proves superior to control, the lower dose will advance to the next phase. The entire study will stop if no dose proves superior to control during the lead-in phase.  The definitive phase will continue with the 1 selected dose of 3K3A-APC from the lead‑in phase. Approximately 1040 subjects will be randomized during the definitive phase. Subjects from the lead-in phase who receive the dose selected for the definitive phase will be included in the final data analysis.

  Study Sponsor and Lead Investigator:
  Patrick D. Lyden, MD, FAAN, FAHA, University of Southern California

  Other Collaborators:
  ZZ Biotech LLC
  The National Institute of Neurological Disorders and Stroke (NINDS) - 1U01NS100699-01A1
  NIH StrokeNet National Coordinating Center at the University of Cincinnati
  NIH StrokeNet National Data Management Center at Medical University of South Carolina

  US FDA IND#:  103,728

  ClincalTrials.gov identifier:  NCT05484154

  
  

• MOST: MULTI-ARM OPTIMIZATION OF STROKE THROMBOLYSIS STROKE TRIAL

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  NEWS & PRESS RELEASE: https://www.bizjournals.com/cincinnati/news/2018/06/01/uc-lands-largest-grant-ever-for-emergency-medicine.html

  Trial Summary:

  The goal of this study is to determine the effectiveness of combining a drug known as tissue plasminogen activator, or tPA, with blood thinners argatroban or eptifibatide.  The research will look at whether combining tPA with either argatroban or eptifibatide will produce better results in stroke patients in the first 90 days after suffering a stroke versus tPA with a placebo.

  The plan is for 110 hospitals to take part in the study through NIH StrokeNet, the University of Cincinnati based National Coordinating Center for all stroke trials funded by the National Institute of Neurological Disorders and Stroke. 

  Trial Design and Outcomes: 

  This is a three-arm, adaptive, Phase-3, blinded, randomized controlled clinical trial at approximately 110 sites in the United States.  The first 150 subjects will be randomized in a 1:1:1 to treatment.  From 150-500 patients, response adaptive randomization (RAR) will favor the treatment arm showing the greatest benefit based on accrued data.  After 500 patients, one or both intervention arms may be carried forward for fixed randomization versus IV tPA.  A maximum of 1200 patients will be enrolled.

   Eligible patients will be aged 18 or older, receive IV tPA within three hours of symptom onset, and receive study drug (placebo, argatroban or eptifibatide) within an hour of IV tPA.  Endovascular therapy will be per standard of care as needed.

  The primary safety objective of the MOST trial is to determine the safety of combining IV tPA with argatroban or eptifibatide as compared to IV tPA alone, as measured by symptomatic intracranial hemorrhage (sICH) within 36 hours from onset.

  • Study Aim: Confirm safety and establish efficacy of IV tPA plus IV argatroban OR IV tPA plus IV eptifibatide over standard IV tPA alone for acute ischemic stroke
  • Primary Efficacy Endpoint: 90-day functional outcome as measured by the mRS translated into utilities
  • Primary Safety Endpoint: sICH rate (overall and ET-specific)
     

  Study Sponsor and Chair:  
  Opeolu Adeoye, MD MS (Lead), University of Cincinnati

  Collaborating Investigators:
  Andrew Barreto, MD MS, University of Texas Houston
  Joseph Broderick, MD, University of Cincinnati
  Colin Derdeyn MD, University of Iowa
  James Grotta, MD, Memorial Hermann Hospital Houston

  Other Collaborators:
  The National Institute of Neurological Disorders and Stroke (NINDS) - 1U01NS100699-01A1
  NIH StrokeNet National Coordinating Center at the University of Cincinnati 
  NIH StrokeNet National Data Management Center at Medical University of South Carolina

  US FDA: IND # 63550
  

  For More information:
  Department of Emergency Medicine
  University of Cincinnati
  231 Albert Sabin Way
  ML 0769
  Cincinnati, OH 45267
  Email:                    ­­­­­­­­­opeolu.adeoye@uc.edu
  Telephone:          S. Iris Deeds, CCRP @ 513-558-8627

   ClinicalTrials.gov Identifier: NCT03735979 

  
  

• DEFUSE 3: ENDOVASCULAR THERAPY FOLLOWING IMAGING EVALUATION FOR ISCHEMIC STROKE 3

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  This trial enrolled it's last patient May 23, 2017 - Enrollment is now closed
  DEFUSE3 Results
  
  Trial Summary:

  DEFUSE 3 is a prospective randomized Phase III multicenter controlled trial of patients with acute ischemic anterior circulation strokes due to large artery occlusion treated between 6-16 hours of stroke onset with endovascular thrombectomy therapy vs. control. The primary endpoint, the modified Rankin Score, will be assessed at 3 months. The patients’ participation in the study concludes at that time (3 months from stroke onset). The study will randomize up to 476 patients over 4 years. The purpose of DEFUSE 3 is to assess the safety and efficacy of thrombectomy in carefully selected patients in an extended time window. Only the devices listed in this protocol will be used. Selection of the specific device (or devices) is determined by the individual endovascular therapist.

  Trial Design Summary:

  DEFUSE 3 is a prospective randomized Phase III multicenter controlled trial of patients with acute ischemic anterior circulation strokes due to large artery occlusion treated between 6-16 hours of stroke onset. Patients who meet the inclusion criteria will undergo either CT Perfusion/CTA or MR DWI/PWI/MRA studies prior to randomization. Patients who have evidence of an ICA or MCA M1 occlusion and a Target Mismatch Profile will be randomized in a 1:1 ratio to treatment with one or more DEFUSE 3 approved thrombectomy devices (only the devices listed in this protocol are approved for use in DEFUSE 3) plus standard medical therapy versus standard medical therapy alone. Patients who are enrolled, but not randomized, will receive standard therapy according to local guidelines. Baseline data, and information about early stroke therapies, will be captured for this group of patients.

  Randomization of a maximum of 476 patients is planned. A novel adaptive design (see below) will identify, at interim analyses, the group with the best prospect for showing benefit from endovascular treatment, based on baseline core lesion volumes and the times since stroke onset. Interim analyses will be conducted at 200 and 340 patients, at which time the study may stop for efficacy/futility, or the inclusion criteria may be adjusted in the case of futility.

  Sponsors and Collaborators:
  Sponsor: Gregory Albers, MD Stanford University

  Awarded Investigators:
  Protocol Director: Gregory Albers, MD - Stanford University
  Protocol Director: Michael Marks, MD - Stanford University
  Protocol Director: Maarten Lansberg, MD, PhD - Stanford University

  Collaborators: The National Institute of Neurological Disorders and Stroke (NINDS) U01 NS092076
  NIH StrokeNet National Coordinating Center at the University of Cincinnati
  NIH StrokeNet National Data Management Center at Medical University of South Carolina

  FDA, IDE: # G150028

  For More information:
  Stanford University, Stanford Stroke Center
  780 Welch Rd. Suite CJ350, Stanford, CA 94304
  Email: strokecenter@med.stanford.edu
  Telephone: Stephanie Kemp- 650-723-4481

  ClinicalTrials.gov Identifier: # G150028
  
  Article: 
  ​Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging

• MISTIE III: MINIMALLY INVASIVE SURGERY PLUS rt-PA FOR ICH EVACUATION

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  This trial enrolled it's last subject on August 15, 2017 - Enrollment is now closed
  Trial Results
  
  
  
  Trial Summary:

  Does faster clot removal give better patient outcomes in ICH? The MISTIE III intervention seeks to remove blood from the brain through minimally invasive surgery and intermittent dosing of a clot-busting drug, a recombinant tissue plasminogen activator (rt-PA) called alteplase, sold under the tradenames of Cathflo Activase by Genentech in the US and as Actilyse by Boehringer Ingelheim in Europe and Asia. The study premise is that by removing the blood clot faster, injury to the brain will be reduced and the patient’s long-term prognosis will improve.

  Trial Design Summary:

  Primary Objectives: Efficacy: Demonstrate that minimally invasive surgery (MIS) plus recombinant tissue plasminogen activator (rt-PA) for three days improves functional outcome by a 12% increase in the modified Rankin Scale (mRS) score 0-3 compared to medically treated subjects assessed at 180 days. Safety: Demonstrate that early use of MIS+rt-PA for three days is safe for the treatment of ICH relative to rates of mortality, rebleeding, and infection in the medically treated subject at 30 days. Secondary Objective: Demonstrate that the end of treatment volume and percent of ICH reduction from MIS+rt-PA is related to improved functional outcome, as compared to medically treated subjects.

  Study Sponsor and Chair: Daniel F. Hanley, MD, Johns Hopkins University
  Principal Investigator: Mario Zuccarello, MD, University of Cincinnati
  Principal Investigator: Issam Awad, MD, University of Chicago

  Collaborators: National Institute of Neurological Disorders and Stroke (NINDS), Cooperative Agreement: 1U01NS080824-01A1
  Genentech
  Emissary International LLC

  FDA, IDE:

  For More information:

  • ClinicalTrials.gov Identifier: NCT01827046,http://clinicaltrials.gov/ct2/show/NCT01827046?
  • Trial WebSite: http://braininjuryoutcomes.com/mistie-iii-about

• iDEF: STUDY OF DEFEROXAMINE MESYLATE IN INTRACEREBRAL HEMORRHAGE

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  This Trial enrolled it's last subject on November 10, 2017 - Enrollment is now closed.
   Trial Results
   Trial Results PubMed
  
  Trial Summary:

  The focus of this study is to evaluate the investigational drug, deferoxamine mesylate or deferoxamine. This drug removes iron. Blood in the brain after a brain hemorrhage contains iron and this iron damages the brain. We are studying whether removal of iron from the brain hemorrhage will reduce the effects of the brain hemorrhage. We will look specifically at a person’s ability to function well and to think well after a brain hemorrhage. We will also learn more about the safety of the investigational drug.

  Trial Design Summary:

  This is a prospective, multi-center, double-blind, randomized, placebo-controlled, phase II, clinical trial. The main objectives are:

  • To assess whether it is futile to move the iron chelator deferoxamine mesylate forward as a therapeutic intervention for intracerebral hemorrhage (ICH) into Phase III evaluation
  • To assess the safety of deferoxamine intravenous infusions (at a dose of 32 mg/kg/day), given for 3 consecutive days, in a large cohort of ICH patients

  Approximately 294 subjects with spontaneous ICH will be randomized within 24 hours of ICH onset to receive either deferoxamine or placebo for 3 consecutive days. Randomization will control for baseline ICH score; ICH onset-to-treatment time; baseline ICH volume; baseline NIHSS; and concurrent use of warfarin at ICH onset. The proportion of subjects with good outcome at 90 days in deferoxamine-treated subjects will be compared to that of placebo-treated subjects in a futility analysis. Good functional outcome will be defined as modified Rankin Scale score of 0-2.

  Study Sponsor and Chair: Magdy Selim, MD,PHD Beth Israel Deaconess Medical Center

  US FDA, CDER: IND # 77,306

  For More information:

  • ClinicalTrials.gov Identifier: NCT02175225 for more information Link:http://clinicaltrials.gov/ct2/show/NCT02175225?
  • Questions: Magdy Selim, MD, PhD (mselim@bidmc.harvard.edu)