Handbook of Neuroemergency Clinical Trials

Handbook of Neuroemergency Clinical Trials

Second Edition

Editors

Brett E. Skolnick

Celgene Corporation, San Diego, CA, United States

Hofstra Northwell School of Medicine, Manhassett, NY, United States

Wayne M. Alves

Evoke Pharmaceuticals, Inc., Solana Beach, CA, United States

Table of Contents

Cover image

Title page

Copyright

Dedications

List of Contributors

Introduction

Part I. Acute Ischemic Stroke

Chapter 1. Acute Ischemic Stroke

Introduction

Trials of Reperfusion Therapies for Ischemic Stroke

Antithrombotic Drugs

Neuroprotective Drugs in Acute Ischemic Stroke

Stumbling From the Bench to Bedside

Physiological Modification of the Ischemic Environment

Conclusions

Chapter 2. Subarachnoid Hemorrhage

Characteristics of the Disease

Guidelines for Management of Subarachnoid Hemorrhage

Successes and Disappointments

Subpopulations and Outcomes and Their Assessment

Biomarkers and Surrogate Endpoints

Pharmacokinetics and Pharmacodynamics

Consensus Regarding Failures and Possible Solutions

Current State of Practice in Design and Analysis of Randomized Controlled Trials for Subarachnoid Hemorrhage

Disclosures

Chapter 3. Clinical Trials in Spontaneous Intracerebral Hemorrhage

Introduction

Hematoma Growth

Neuroprotection

Surgery

Conclusions

Chapter 4. Imaging Biomarkers in Stroke Trials

Introduction and Description of Imaging Biomarkers

Imaging of Intraluminal Thrombus

Vascular Imaging

Collateral Arterial Supply

Ischemic Core and Penumbra

Predictive Versus Prognostic Biomarkers

Utility of Imaging Biomarkers

Conclusions and Future Directions

Part II. Traumatic Brain Injury

Chapter 5. Traumatic Brain Injury

Introduction

Historical Context of Traumatic Brain Injury Trials

Drug Development Programs for Traumatic Brain Injury

Drugs and Treatments Tested to Date for Traumatic Brain Injury

Ion Channel Blockers

Why Have Traumatic Brain Injury Trials Proven to Be So Difficult?

Key Issues in Traumatic Brain Injury Clinical Trial Design

Conclusions

Chapter 6. Improving Approaches to Evaluate Efficacy and Safety of Drugs for Traumatic Brain Injury

Translational Approaches

Improving Trial Design and Analysis

Alternative Strategies to Exploring Clinical Efficacy

Chapter 7. Brain Imaging in Traumatic Brain Injury

Introduction

Types of Brain Injuries

Classification of Traumatic Brain Injury

Implications and Challenges for Clinical Trials

Conclusion

Chapter 8. The Use of Blood-Based Biomarkers to Improve the Design of Clinical Trials of Traumatic Brain Injury

Introduction

Summary of Search of Clinical Trials in Traumatic Brain Injury Using Biomarkers

Surrogate Endpoints and Selection of Central Nervous System–Specific Protein Biomarkers for Severe Traumatic Brain Injury Diagnostics

Discussion

Prospects and Pathways for Incorporation of Blood-Based Biomarkers Into the Design of Clinical Trials for Traumatic Brain Injury

Chapter 9. Biostatistical Issues in TBI Clinical Trials

Introduction

Clinical Trial Design

Approaches to Randomization

Outcome Measures

Analytical Approaches

Missing Data

Multiplicity

Subgroup Analysis

Assessments Conducted Over Time

Heterogeneity of the Patient Population

Summary

Part III. Seizure Emergencies

Chapter 10. Acute Seizures and Status Epilepticus

Overview

Diagnosis and Definition of Status Epilepticus

Classification of Status Epilepticus

Animal Models: Relevant Issues for Clinical Development Programs

Epidemiology and Natural History

Mechanisms of Disease and Pathology

Diagnosis and Subpopulations

Current Disease Management and Controversies

Issues in Clinical Protocol Development

Outcome Measures

Surrogate Endpoints

Safety Evaluation

New Trials and Potential Challenges

Conclusion

Chapter 11. Posttraumatic Seizures

Introduction

Clinical Definitions

Clinical and Genetic Risk Factors for Posttraumatic Seizures

Mechanisms of Posttraumatic Epileptogenesis

Animal Models of Posttraumatic Epilepsy

Clinical Trials for Prevention of Posttraumatic Seizures

Management of Late Posttraumatic Seizures

Future Directions: Clinical Trial Considerations for Antiepileptogenic Agents

Part IV. Nontraumatic Neuroemergencies

Chapter 12. Neuroemergencies in Critical Care Patients

Approach to the Neurological Exam

Alterations in Mental Status

Meningitis/Encephalitis

Weakness

Spinal Cord Compression

ICU-Acquired Weakness

Cerebrovascular Disease

Acute Ischemic Stroke

Cerebral Hemorrhage

General Stroke Management

Complications From Cerebrovascular Disease

Increased Intracranial Pressure

Vasospasm

Status Epilepticus

Conclusion

Chapter 13. Neuroemergency Clinical Trials: Migraine

Introduction

Ergots

Triptans

Neuroleptics

Nonsteroidal Antiinflammatory Drugs

Opiates and Barbiturates

Other Acute Migraine Treatments

Discussion

Chapter 14. Acute Visual Deficits

Optic Neuritis Treatment Trial

Epidemiology and Natural History

Diagnosis

Current Disease Management

Design Overview

Issues in Clinical Protocol Development

Determination of Outcomes

Outcomes of the Optic Neuritis Treatment Trial

Current Recommendations for Treatment of Acute Demyelinating Optic Neuritis

Results of Clinical Severity Measures

Other Measures and Analyses

Surrogate Endpoints: Development of Clinically Definite Multiple Sclerosis

Implications for Present and Future Treatment of Multiple Sclerosis

Idiopathic Intracranial Hypertension Treatment Trial

Rationale for the Idiopathic Intracranial Hypertension Treatment Trial

Design Overview

Visual Function Assessments

Outcomes of Idiopathic Intracranial Hypertension Treatment Trial

Primary and Secondary Outcomes of Acetazolamide Therapy

Adverse Events

Optical Coherence Tomography Ancillary Study

Conclusions

Part V. Devices for Neuroemergencies

Chapter 15. Implications for New Trials in Acute Ischemic Stroke in the New Era of Endovascular Therapy

Tissue Window for Patient Selection

Geographic and Systems of Care Implications

Human Ischemia-Reperfusion Model

Optimizing Interventional Techniques

New Standards for Acute Ischemic Stroke Trials

Part VI. Key Issues in Neuroemergency Clinical Trials

Chapter 16. The Role of a Project Medical Officer in Acute Neuroemergency Clinical Studies

Project Medical Officer Qualifications

Assess Compound Characteristics, Preclinical, and Toxicology Data

For Devices: Review Design History File; Assess Device Hazards and Harms; Ensure Medical Issues Are Addressed in Device Instructions for Use

Compile/Contribute to the Investigator Brochure

Study Design and Protocol Creation

Consult With Key Opinion Leaders

Assess Study Feasibility, Timelines, and Budget

Review of Case Report Forms and Case Report Forms Completion Guidelines

Provide Medical Input to Regulatory Authority Submissions

Draft Informed Consent Form Template

Provide Medical Input to Ethics Committee/Investigation Review Board Submissions

Provide Therapeutic Area Training for Sponsor’s Staff and Contract Research Organization Personnel

Select and Evaluate Sites

Provide Medical Support at Investigator Meetings

Participate in the Site Initiation Process

Monitor Enrollment Rates and Progress to Achieving Completed Subjects Who Will Contribute to the Primary and Secondary Endpoints

Manage Emerging Site Issues During Enrollment and Evaluate Adherence to the Protocol

Answer Hotline Calls

Monitor Protocol Deviations

Review Coding of Medical Events for Adverse Events, Serious Adverse Events, Medical History, and Concomitant Medications

Guiding Serious Adverse Effects and Case Report Forms Completion Issues

Monitor Ongoing Subject Safety, Emerging Safety Profile of the Compound, and Benefit: Safety Assessment

Determine Whether Adverse Events Meet Criteria for Serious and Unexpected Suspected Adverse Reaction or Medical Device Reporting Reportable Event

Represent Study Team at Data Monitoring Committee Open Session

Contributing to and Reviewing the Statistical Analysis Plan and Dummy Output

Writing/Contributing to Clinical Study Report

Chapter 17. Regulatory Considerations

Introduction

Nonclinical Development

Investigational New Drug Applications

Communicating With FDA

The Role of the Core Data Sheet

Expedited Development Programs

Orphan Drug Designation

Study Considerations

Marketing Authorization

Postmarketing

Conclusion

Chapter 18. Military Perspectives on Brain Injuries: Implications on Clinical Trials

Introduction

Conducting Military Medical Research

Epidemiology and Autopsy

Hemorrhage

Traumatic Brain Injury

Posttraumatic Stress Disorder

Traumatic Amputations

Burn Injuries

Eye Injuries

Infectious Diseases

New Technologies for Austere Environments

Conclusions

Index

Copyright

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Notices

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Dedications

Skolnick

Inspiration for the creation of this second edition of the Handbook of Neuroemergency Clinical Trials was a result of the impressive updates to the treatment of ischemic stroke with the approval of a variety of interventional devices that complement or serve as an alternative to the only current approved therapeutic, Activase. The collaboration of the many clinical scientists was a critical requirement to create this advance in management of this acute neurologic disease. Over the years, I have had the opportunity to interact and learn from my colleagues first at the University of Pennsylvania who provided the critical foundations for my study of acute neurologic diseases over three  decades ago. More recently, my work at Novo Nordisk continued my opportunity to work with dedicated colleagues in the areas of intracerebral hemorrhage and traumatic brain injury. This adventure now continues as we work to bring new and innovative therapies to the neuroscience community as the journey continues with my new colleagues at Receptos/Celgene.

A special thanks to my family, Mary Ann Crawford and Maxwell C. Skolnick for providing their unconditional support.

Alves

In memory of John A. Jane, Sr., MD, PhD and Anthony Marmarou, PhD

List of Contributors

Timothy I. Alves,     University of Michigan, Ann Arbor, MI, United States

Wayne M. Alves,     Evoke Pharmaceuticals, Inc., Solana Beach, CA, United States

Hans Bakken,     Stanford University, School of Medicine, Stanford, CA, United States

Laura J. Balcer,     New York University Langone Medical Center, New York, NY, United States

Thomas Berk,     New York University School of Medicine, New York, NY, United States

Christopher F. Bladin,     Eastern Melbourne Neurosciences (Monash University), Box Hill Hospital, Melbourne, VIC, Australia

Thomas P. Bleck,     Rush Medical College, Chicago, IL, United States

Bruce C.V. Campbell,     University of Melbourne, Melbourne, VIC, Australia

Shamik Chakraborty,     Hofstra-Northwell School of Medicine, Manhasset, NY, United States

Stephen M. Davis,     University of Melbourne, Melbourne, VIC, Australia

Geoffrey A. Donnan,     University of Melbourne, Melbourne, VIC, Australia

Nicole Draghic,     Biostar Group, Inc., Germantown, MD, United States

James Ecklund,     Inova Fairfax Hospital, Fairfax, VA, United States

Alexander V. Glushakov,     University of Florida College of Medicine, Gainesville, FL, United States

Olena Y. Glushakova,     Virginia Commonwealth University School of Medicine, Richmond, VA, United States

Mayank Goyal,     University of Calgary, Calgary, AB, Canada

Jared A. Greenberg,     Rush Medical College, Chicago, IL, United States

Jamie Grimes,     Uniformed Services University of Health Sciences, Bethesda, MD, United States

Clotilde Hainline,     New York University Langone Medical Center, New York, NY, United States

Ronald L. Hayes

Virginia Commonwealth University School of Medicine, Richmond, VA, United States

Banyan Biomarkers, Inc., Alachua, FL, United States

Susan T. Herman,     Harvard Medical School, Boston, MA, United States

Michael D. Hill,     Foothills Hospital, Calgary, AB, Canada

Jessalyn K. Holodinsky,     University of Calgary, Calgary, AB, Canada

Steven B. Johnson,     Medpace, Inc., Cincinnati, OH, United States

Brad J. Kolls,     Duke University Medical Center, Durham, NC, United States

Daniel T. Laskowitz,     Duke University Medical Center, Durham, NC, United States

Howard Levy,     Howard Levy Consulting LLC, Hopewell, NJ, United States

Geoffrey Ling,     Uniformed Services University of Health Sciences, Bethesda, MD, United States

Alexandra Lloyd-Smith,     New York University Langone Medical Center, New York, NY, United States

Andrew I.R. Maas,     Antwerp University Hospital and University of Antwerp, Edegem, Belgium

Robert Loch Macdonald,     University of Toronto, Toronto, ON, Canada

Rebekah Mannix,     Harvard Medical School, Boston, MA, United States

Lawrence F. Marshall,     University of California San Diego, San Diego, CA, United States

Stephan A. Mayer,     ICAHN School of Medicine at Mount Sinai, New York, NY, United States

David K. Menon,     University of Cambridge, Cambridge, United Kingdom

Emmy R. Miller,     Virginia Commonwealth University School of Medicine, Richmond, VA, United States

Raj K. Narayan,     Hofstra Northwell School of Medicine, Manhasset, NY, United States

Yuko Y. Palesch,     Medical University of South Carolina, Charleston, SC, United States

Fred Rincon,     Thomas Jefferson University, Philadelphia, PA, United States

Janet C. Rucker,     New York University Langone Medical Center, New York, NY, United States

Stephen D. Silberstein,     Jefferson University Hospitals, Philadelphia, PA, United States

Brett E. Skolnick

Celgene Corporation, San Diego, CA, United States

Hofstra Northwell School of Medicine, Manhassett, NY, United States

Madhura A. Tamhankar,     University of Pennsylvania School of Medicine, Philadelphia, PA, United States

Nancy Temkin,     University of Washington, Seattle, WA, United States

Alex B. Valadka,     Virginia Commonwealth University School of Medicine, Richmond, VA, United States

Max Wintermark,     University of Virginia, Charlottesville, VA, United States

Sharon D. Yeatts,     Medical University of South Carolina, Charleston, SC, United States

Charlotte Zerna,     University of Calgary, Calgary, AB, Canada

Introduction

Brett E. Skolnick, and Wayne M. Alves

The second edition of the Handbook of Neuroemergency Clinical Trials is intended to draw attention to the important work that has transpired over the past decade particularly in the area of interventions in ischemic stroke and traumatic brain injury. In the latter part of the 20th century scientific advances in understanding the mechanisms and pathophysiology of acute central nervous system injury, especially the neurochemical cascade associated with secondary brain injuries figured prominently with stroke and trauma, and provided significant attention to a variety of putative therapeutic agents that were anticipated to improve neurologic outcomes. However, this excitement was offset by a history of disappointing results from clinical trials of an unprecedented number of novel neuroprotective drugs. The list of apparently ineffective compounds includes free radical scavengers, calcium channel blockers, and glutamate NMDA-receptor antagonists along with many other classes of molecular targets. Were these disappointments reflective of failure of our therapeutic hypotheses, or our inability to provide a relevant target population for investigation? Or were these disappointments a result of complexity added by our blunt assessment instruments, the absence of documented brain penetrance, and clinical settings that were inappropriate? All of which resulted in a series of systematic failures.

The focus of this volume is the state of the practice of clinical trials in acute neuroscience populations or neuroemergencies. The book is intended to focus on what has transpired over the past decade and how the use of biomarkers, inclusive of new imaging methodologies, have provided a more precise means of identifying target populations for study.

We entered the 1990s, the Decade of the Brain as the clinical epidemiology of acute neuroemergencies was becoming better understood. High incidence, potentially devastating consequences, recognition of the complexity of damage and outcome making the patients the sickest of the sick, with little or no effective treatments beyond supportive management, and improved neurosurgical and neurointensive care management. This was combined with an unparalleled optimism regarding the potential of novel neuroprotective compounds. The Decade of the Brain left a trail of disappointment as a legacy of failed clinical trials emerged. While disappointments have been many, recent work to organize consortiums to handle the complexity of neuroemergency clinical trials offer hope and include support for IMPACT¹ and NeuroNEXT², an NINDS initiative to design and conduct exploratory trials in acute neurological conditions.

While neuroemergencies have a fairly high incidence (e.g., stroke is a leading cause of severe disability in the United States; TBI is the leading cause of death among patients under 45  years of age and accounts for nearly a third of trauma-related deaths in the United States), they are relatively rare in comparison to non-CNS diseases. They also carry with them significant risk for devastating complications and slow recovery. These are complex diseases and disorders with no singular recovery pattern. In some cases, similar injuries appear to have different outcomes, while in other cases the same outcomes result from quite different injuries. Morbidity is often underestimated, and factors of lifestyle and life cycle are important in both etiology and recovery. Neuroemergencies that are even less frequent or perhaps of milder severity (e.g., mild TBI) often have profound morbidity consequences, which make their occurrence a fairly significant public health issue. There is a great opportunity to explore the value a mild TBI program could have within the current scientific and drug development landscapes. Further, how can we de-risk a mild TBI neuroprotection program using clinically leveraged models and potentially lower hurdles to approval?

By the mid-1990s over 100 NCEs were under development for a number of neurological disease indications, including about a dozen for traumatic brain injury. In spite of the focus of the Decade of the Brain, we still have no approved drugs for TBI, and only a single compound (r-TPA) has been approved for use in ischemic stroke. This disappointing experience makes clear that safe and effective drugs in the neuroemergency area would be difficult and that success would be incremental. The problem, we are coming to understand, is how to better define our patient populations, whether they be acute ischemic stroke, traumatic brain injury, or other neuroemergency settings and how best to characterize an optimal patient population for possible therapeutic intervention. This appears critical in that it has been recognized that there are multiple processes underlying the ultimate damage that results and that are outcome measures are fairly blunt instruments for assessment.

The purpose of this volume is to explore the issues we face and to develop strategies that might lead to future success in developing therapeutic approaches for neuroemergencies, which remains a critical area of unmet medical needs. In retrospect, in our evaluation of past neuroemergency development programs we are tempted to attribute our failures as the result of skipping steps in the drug development process. This does not mean we should not strive to be creative in defining the optimal drug development paradigm for specific neuroemergency indications. The conventional drug development process is a staged, sequential process that clinical development scientists have long sought to reengineer and streamline. But the answer goes beyond simply the logistics of drug development. Our ability to define relevant treatment populations and measure the effects of treatment interventions is equally important. Improved disease classifications based on pathology and the use of continually improving imaging methods, improved endpoint measurement and analysis, identification of leveraged in vivo models to provide for better proof-of-concept studies, development of validated endpoints, and innovative clinical trials methodologies all can contribute to future success.

The minimal target criteria for a successful neuroprotectant are not difficult to describe. It must be safe, reach an intended action site (i.e., cross the blood–brain barrier), have an expected neurochemical effect, produce an expected neurophysiological effect leading to functional changes, and thereby improve clinical outcomes. The issue is how to demonstrate this in the context of adequate and well-controlled clinical trials.

Current Status of Treatment of Neuroemergencies

The brain is a small, somewhat round object weighing approximately three pounds. As an organ, it has unique vulnerabilities. Its energy requirements demand a constant blood supply providing glucose and oxygen substrates. The brain is the organ most prone to spontaneous hemorrhage, and second most prone to symptomatic ischemic infarction. Cerebral arteries are thinner and less elastic than in other systems of the body. Injury produces not only neurophysical impairments but also changes in intellectual, emotional, and personality function.³

While the mechanisms of damage (e.g., infarction, hemorrhage, contusion, or edema) in neuroemergencies are limited, they seldom occur in isolation. It is often the case that several pathophysiological mechanisms are combined.³,⁴ This multiplicity of pathways for damage and outcome may be a major contributing reason for the failure of clinical trials. The characteristic mechanisms of acute brain injury (listed below) are limited and tend to occur in combination with each other to create varying degrees of complexity of damage with impact on clinical outcome:

• Brain edema

• Hemorrhage

• Ischemia and brain swelling

• Hydrocephalus

• Neurotransmitter failure

• Toxic substances that cross blood–brain barrier

• Infection or inflammation

• Brain atrophy

Numerous reasons have been offered for the failure of clinical trials in acute neuroscience disorders including whether the underlying therapeutic hypothesis is flawed, the nature of acute neuroscience populations, whether the drug is able to cross the blood–brain barrier, study design considerations, the clinical populations actually enrolled in the trials, and failure to control relevant disease cofactors. Especially relevant is the adequacy of brain penetration of the investigative agents tested in terms of optimizing dosage and the dosing regimens employed. To address these issues and shortcomings, academic-industry collaboration has tried to define optimal preclinical and clinical strategies for drug development in ischemic stroke (STAIR⁵ Consensus Conferences).

Acute Neuroclinical Trials

There is a relatively limited history of drug development in acute neuroscience populations. As mentioned, the diseases are fairly rare and require more research sites for sufficient enrollment. Individual practice variations in hospital-based settings (e.g., emergency departments or neurological intensive care units) contribute to a plethora of examinations, drugs, and supportive interventions. Treatment decisions are often idiosyncratic and their standards of treatment although much improved in the last decade are still variable across the globe. Consequently, subjective definitions and perceptions are very important in guiding treatment decisions. Guideline statements (ICH: Hemphill⁶; Acute Ischemic Stroke: Jauch⁷) are becoming more robust regarding treatment options and regarding medical management but are still limited by the paucity of treatments. This poses considerable challenges for the design, conduct, and analysis of randomized clinical trials. Because gold standards are few, often there is a lack of consensus on appropriate measurement of damage and clinical outcome measures. Because trials are large, they take time to conduct and analyze and there is a danger that the evolution of standards of clinical care could alter the clinical settings during the conduct of trials.

Many steps might be contemplated in improving neuroemergency trials. Possible improvements in neuroemergency clinical trials methodology that come to mind include the following:

• Focus on clinical benefit and crisper endpoint assessment using validated measures or outcome;

• Consider patient-reported outcome measures for milder severity indications (e.g., mild TBI);

• Clinical phenotyping of treatment populations to avoid including patients with excessively good or excessively poor prognosis;

• Improved assessment of intermediate effects (i.e., biomarkers or mechanistic endpoints) as supportive evidence; and

• Consideration novel approaches to neuroemergency trials design and randomization strategies.

Purpose of This Volume

Modern clinical drug development involves complex interactions among scientific, medical, commercial, regulatory, and manufacturing issues.⁸ This volume is intended to provide developers of novel therapies with a more complete understanding of the scientific and medical issues of relevance in designing and initiating clinical development plans intended for acute neuroscience populations. We hope that we can provide an understanding of the pitfalls associated with drug development in neuroemergencies as well as a single source for the best information available regarding how to approach and solve the issues that have plagued drug development since the early 1990s.

We asked authors to include disorders generally requiring emergency care or intensive care in highly specialized clinical settings (e.g., neurological ICUs). The authors could include discussion of drug development for disorders where the brain is a component and clinical development is primarily focused on brain protection device trials (e.g., endovascular obliteration of cerebral aneurysms, thrombectomy) and brain access technologies where relevant could also be discussed. Out of sheer practicality, we excluded systemic complications in the context of neuroemergencies, e.g., neurogenic cardiovascular disorders or respiratory syndromes, except as they are relevant to understanding the nature of the acute CNS disease and have implications for clinical drug development programs. We also excluded evaluation of neurosurgical interventions per se, and drug development for disorders where the brain is a disease component but the therapeutic focus is on the systemic disease. The mandate to authors was to focus on relevant aspects of their respective disease areas that bore importance to the design and analysis of clinical trials.

No single volume can do justice to the complexity of drug development in acute neuroscience populations. We hope that this second edition provides an opportunity to stimulate discussions that may lead to innovative solutions to the problems that have plagued the search for safe and efficacious therapeutic agents in the acute neurologic area. It is our aim with this edition to provide investigators with the tools and the historic perspectives that will foster the development of new approaches that can begin to solve the issues that have hampered drug development in the neuroscience arena for many years.

This second edition will present the impressive changes in the management of acute ischemic stroke that have occurred in recent years. This resulted from the systematic work done in collaboration with the departments of neuroradiology, neurosurgery, neurology, and with the advent of the neurointerventionalist in collaboration with medical device developers. These disciplines have provided for the careful evaluation and selection (or enrichment) of relevant target populations for the new methods/devices capable of removing clots that have impaired cerebral blood flow. These dedicated clinicians/scientists have altered the outcomes of acute cerebral vascular events. A similar process needs to be encouraged in the area of TBI where the heterogeneity of patient groups, blunt instruments for assessing outcomes and perhaps less interdisciplinary collaboration, to date, has limited the development of new therapeutics. The careful work continues and will ultimately result in overall improved clinical outcomes based on general enhancements in medical management. The next steps are to develop and enhance the tools needed to evaluate interventions in this clinical setting.

References

1. Maas A.I, Murray G.D, Roozenbeek B, et al. Advancing care for traumatic brain injury: findings from the IMPACT studies and perspectives on future research. Lancet Neurol. 2013;12:1200–1210.

2. NeuroNEXT: Accelerating drug development in neurology. Lancet Neurol. 2012;11(2):119.

3. Becker D.P, Gudeman S.K, eds. Textbook of head injury. Philadelphia: W.B. Saunders Company; 1989.

4. Cruz J, ed. Neurologic and neurosurgical emergencies. 1st ed. Philadelphia: W.B. Saunders; 1998.

5. Stroke therapy academic industry roundtable (STAIR): http://www.thestair.org.

6. Hemphill J.C, Greenberg S.M, Anderson C.S. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015;46(7):2032–2060.

7. Jauch E.C, Saver J.L, Adams H.P. Guidelines for the early management of patients with acute ischemic stroke. Stroke. 2013;44(3):870–947.

8. Steiner J. Clinical development: strategic, pre-clinical, clinical, and regulatory issues. Taylor & Francis; 1996.

Part I

Acute Ischemic Stroke

Outline

Chapter 1. Acute Ischemic Stroke

Chapter 2. Subarachnoid Hemorrhage

Chapter 3. Clinical Trials in Spontaneous Intracerebral Hemorrhage

Chapter 4. Imaging Biomarkers in Stroke Trials

Chapter 1

Acute Ischemic Stroke

Bruce C.V. Campbell, Christopher F. Bladin, Geoffrey A. Donnan, and Stephen M. Davis

Abstract

Major progress has occurred in the therapy of ischemic stroke, predominantly in the field of reperfusion with intravenous thrombolysis and endovascular thrombectomy. Challenges remain in implementation with underutilization of thrombolysis and rapidly evolving systems for delivery of endovascular thrombectomy, which brings new resource challenges. Multiple trials of putative neuroprotective compounds have been disappointing but there is new enthusiasm in the era of highly effective endovascular reperfusion and more rigorous preclinical evaluation.

Keywords

Endovascular thrombectomy; Intraarterial therapy; Ischemic stroke; Neuroprotection; Thrombolysis

Introduction

Stroke is one of the most devastating diseases of Western society. Stroke is a leading cause of death and disability.¹ The social and psychological costs are enormous, and the health economic costs run into billions of dollars. Developing successful and reliable acute treatments for stroke has been a story of mixed successes with major progress in reperfusion therapies contrasting with repeated failure of neuroprotective strategies.

Trials of Reperfusion Therapies for Ischemic Stroke

Intravenous recombinant tissue plasminogen activator (tPA, alteplase) was approved for use in acute stroke within 3  h of stroke onset in the United States of America in 1996 following publication of the landmark National Institute of Neurological Disorders and Stroke (NINDS) stroke study in the New England Journal of Medicine.² Approval for the use of alteplase in acute stroke followed in Canada (1999), Europe (2002), and Australia (2003). Several other trials using a more extended 0–6  h time window were neutral overall.³–⁶ However, a series of individual patient data metaanalyses have established clear benefit of alteplase to reduce disability when administered within 4.5  h of stroke onset.⁷–⁹ The European Cooperative Acute Stroke Study 3 (ECASS 3) trial required by European licensing authorities confirmed benefit in this 3–4.5  h window which is now recognized in stroke guidelines worldwide.¹⁰ The US FDA has, however, refused to extend the license from 3 to 4.5  h in the United States. The benefits and risks of alteplase in acute stroke are now well understood in the stroke community but still the subject of debate among some groups of emergency physicians, which has unfortunately impaired the uptake of intravenous thrombolysis in areas not well served by stroke specialists.¹¹,¹² Debate around differences in trial methodology, outcome measures, and perceived financial conflicts of interest is discussed below. The British Medical Journal website has posted the many contributions to this often heated discussion.¹¹

To fully understand the issues involved in the use of alteplase in stroke, it is worth undertaking a brief overview of the seminal trials undertaken, and follow this with discussion on the phase 4 (postmarketing) studies of alteplase in acute stroke, otherwise known as alteplase use in the real world.¹³

While alteplase clearly improves patient outcomes, its effectiveness in large vessel occlusion is limited. The field of stroke reperfusion therapy has therefore been transformed by the publication in 2015 of five positive trials of endovascular thrombectomy,¹⁴–¹⁸ which is highly effective in achieving rapid reperfusion in large vessel occlusion patients. These trials will be discussed in detail.

Stroke Alteplase Thrombolysis Trials

The NINDS tPA Trial

The NINDS tPA study was published in 1995.² Acute ischemic stroke patients were treated with alteplase or placebo within 3  h of symptom onset. Those receiving alteplase achieved greater neurological recovery and experienced less disability that patients who received placebo. The alteplase dose was 0.9  mg/kg (maximum 90  mg), and half of the patients were treated within 90  min of stroke onset. Patients in this study had moderately severe strokes with a median baseline score National Institutes of Health Stroke Scale (NIHSS) of 14 for alteplase-treated patients and 15 for the placebo group. There was a strict protocol for managing hypertension, and all patients were admitted to the intensive care unit for the first 24  h. Outcome measures were based on a global outcome score. This was a composite endpoint based on four disability scales (Barthel, Glasgow Outcome Scale, Rankin, and NIHSS) to detect a consistent and persuasive difference in the proportion of patients achieving a favorable outcome. At 3  months, each of the four primary outcome scales and the combined global tested statistics demonstrated statistically significant benefit for the use of alteplase. In summary, 42% of the alteplase-treated patients and only 26% of the placebo-treated patients had regained functional independence at 3  months. Overall, six patients (95% CI: 5–11) had to be treated for one additional patient to recover functional independence, and nine patients (95% CI: 5–25) had to be treated for one additional patient to achieve full neurological recovery.¹³ The beneficial effects occurred in patients with all subtypes of stroke, including lacunar infarction. Further analysis of the NINDS data set revealed that the benefits were sustained at 1  year with no additional increase in mortality.¹²

The occurrence of intracranial hemorrhage is the complication of most concern with alteplase treatment. Some hemorrhagic transformation is part of the natural history of ischemic stroke evolution¹⁹ and most is asymptomatic (usually of small size without mass effect). However, symptomatic intracranial hemorrhages (SICH) can occur with development of large parenchymal hematoma with mass effect and clinical deterioration. In the NINDS study, a liberal definition of SICH was used (any intracerebral bleeding in association with any neurological deterioration), and this occurred in 6.4% of the alteplase-treated patients, and 0.6% of the placebo patients (P  ≤  .01).²⁰ Most alteplase-related hemorrhages occurred within the first 24  h and nearly half were fatal. The risk factors for developing intracerebral hemorrhage included increased stroke severity (NIHSS score) and hyperglycemia. Although the European alteplase trials⁵,⁶ suggested that baseline CT findings of early cerebral edema with mass effect predicted hemorrhagic transformation with alteplase, reanalysis of the NINDS trial did not suggest any major association.²¹ Despite the tenfold difference in rate of SICH, the all cause mortality rate was 17% for alteplase-treated patients and 21% for placebo patients (not statistically significant) with no increase in mortality attributable to alteplase within the first week or first 3  months.

Another antithrombolysis argument that has been put forward is that some patients are rescued from death due to stroke only to be left with severe disability. However, the improved outcome in alteplase patients was not associated with an increase in the number of patients surviving with severe disability.²

The NINDS tPA trial has undergone considerable scrutiny and interpretation since publication in December 1995. An imbalance in baseline stroke severity between the alteplase and placebo treatment groups has been the primary focus of discussion.¹¹,²²,²³ When the baseline NIHSS scores were divided into quintiles (0–5, 6–10, 11–15, 16–20, >20), it was found that imbalances existed in the mildest and most severe stroke groups. Of the 58 patients in the 0–5 NIHSS group, 42 (72%) were in the alteplase treatment group versus 16 (28%) in the placebo treatment group. Among the 140 patients in the >20 NIHSS group, 63 (45%) were in the alteplase treatment group versus 77 (55%) in the placebo treatment group. The imbalance in baseline stroke severity generated concerns that the treatment benefit reported in favor of alteplase may have been explained by the excesses of both mild strokes allocated to alteplase and more severe strokes allocated to placebo.

To determine whether the baseline stroke severity imbalance affected the outcome of the trial, the NINDS appointed an independent committee made up of three biostatisticians and three stroke clinicians to reanalyze the NINDS trial data. In addition to the issue of baseline stroke severity imbalance, the committee was asked to determine whether eligible stroke patients may not benefit from alteplase given according to the treatment protocol used in the trials. After performing extensive analyses, the committee has reported that the baseline stroke severity imbalance did not affect the outcome of the study.²⁴ Indeed, they confirmed in multivariable analysis that there was evidence of a statistically significant alteplase treatment effect. Exploratory analyses did not identify any group of acute ischemic stroke patients who would be harmed by receiving alteplase. Specifically, there was no evidence that either baseline NIHSS or time from stroke onset to treatment modified the alteplase treatment effect.

ECASS 1 and 2 Trials

Studies on alteplase in acute stroke were also undertaken in Europe. The initial two studies performed were the ECASS 1 and ECASS 2.⁵,⁶ In the first ECASS study the dose of alteplase was higher than that used in the NINDS tPA trial, at 1.1  mg/kg with a maximum dose of 100  mg. The other difference was that the window for administration of alteplase was broader at 6  h and the median time to treatment was 4  h. In ECASS 1 there was a 20% incidence of parenchymal hematoma in the alteplase patients. There were a number of possible causes for this including the longer treatment window, the higher dose of alteplase, and, perhaps most importantly, the inclusion of large numbers of patients (almost 1 in 5) with protocol violations. These deviations mainly consisted of the failure to recognize changes on the pretreatment CT scan that should have excluded the patient from inclusion in the study. There was no statistically significant difference in primary outcome where alteplase treated and placebo groups were based on the intention to treat analysis.⁵ In a reanalysis of the ECASS 1 data, excluding patients who were inappropriately included in the study, the proportion of patients with minimal or no disability (modified Rankin scale of 0 or 1) at 3  months was significantly greater in the treatment group than in the control group (41% vs. 29%, P  ≤  .05).

With the many lessons learned during ECASS 1, ECASS 2 was undertaken in the late 1990s. The alteplase dose was reduced to 0.9  mg/kg, as in the NINDS trial. There was extensive training of investigators to recognize the CT abnormalities of early ischemic stroke, in particular, focusing on the exclusion of patients with more than one-third of the middle cerebral artery (MCA) territory involved in the ischemic process on the initial CT scan. Strict blood pressure controls were also implemented.

The primary outcome measure was defined as the proportion of patients with a favorable outcome based on the modified Rankin scale score of 0 or 1 at 3  months, again in keeping with the NINDS trial. Based on this outcome measure, there was no significant difference between alteplase treatment and placebo, although the distribution of mRS scores revealed a benefit in favor of alteplase treatment. A post hoc analysis was then undertaken, in which patient outcomes were dichotomized as either good outcome, as indicated by independence in self-care (mRS score 0–2), or bad outcome, as indicated by death or dependence (mRS score 3–6). A significantly greater proportion of the alteplase-treated patients achieved independence at 3  months (54% vs. 46%, P  =  .024).⁶ From this post hoc analysis, it was determined that 12 patients had to be treated for one additional independent survivor. Intracranial hemorrhage was more common in the alteplase-treated patients (9%) than placebo patients (3%), but again there was no difference in mortality between the two groups.

One of the important points with ECASS 2 was that the time window remained at 6  h, and the results indicated that alteplase reduced disability without increasing the mortality rate. It should be emphasized that the primary outcome of the study was negative, and that a positive result was only achieved after a post hoc analysis with reconfiguring of the methodological definition of favorable outcome.

ATLANTIS Trial

The Alteplase Thrombolysis for Acute Interventional Therapy in Acute Ischemic Stroke (ATLANTIS) study⁴ differed from other alteplase studies in that it experienced a number of protocol changes due to publication of the NINDS trial and had two time windows: Part A (<3  h) and Part B (3–5  h). For Part B there was no clinical benefit and with an increase in mortality. Although the numbers in Part A were small, there was a benefit in this cohort.³

ECASS 3 Trial

The ECASS 3 trial was mandated by the European Medicines Authority to explore the benefit of alteplase 3–4.5  h after stroke onset that had been suggested in individual patient data metaanalysis of the previous trials.¹⁰ The odds ratio for favorable outcome of 1.34 (1.02–1.76) was in line with that of the metaanalysis with a number needed to treat of 14 to achieve an extra patient with independent functional outcome.

EPITHET Trial

This phase 2 trial examined whether thrombolysis could improve outcomes beyond 3  h after stroke onset if MRI demonstrated evidence of salvageable ischemic penumbra.²⁵ Patients were randomized to alteplase versus placebo 3–6  h after stroke onset with baseline perfusion–diffusion MRI obtained prior to treatment but not used to select patients for the trial. Reperfusion, assessed at 3–5  days, was strongly associated with independent functional outcome in patients with a favorable perfusion–diffusion imaging mismatch profile (63% vs. 32%, P  =  .007) and alteplase doubled the rate of reperfusion versus placebo (56% vs. 26%, P  =  .01). However the study was underpowered to assess benefit of tPA on functional outcome. Echoplanar imaging thrombolytic evaluation trial (EPITHET) led to the larger phase 3 extending the time for thrombolysis in emergency neurological deficits (EXTEND) trial that is examining thrombolysis 4.5–9  h after stroke onset and in wake-up onset stroke patients who have favorable perfusion imaging.²⁶

IST-3 Trial

The Third International Stroke Trial (IST-3) enrolled 3035 patients between 2000 and 2011 and had very open clinical inclusion criteria.²⁷ After an initial double-blind phase the majority of patients were treated open label but assessed by blinded clinicians. The primary outcome of functional independence did not reach significance but there was a significant shift toward improved outcome in ordinal analysis of the mRS. This trial contributed the largest number of elderly patients and demonstrated that the alteplase treatment effect was as least as large in those aged over 80  years versus younger patients.

Metaanalyses of Thrombolysis Trials

The completion of multiple randomized controlled trials using alteplase in acute ischemic stroke enabled metaanalyses to be undertaken.⁷–⁹ The most powerful strategy to adjust for differences between trials is individual patient data metaanalysis, and these have revealed an overall benefit for alteplase treatment, regardless of the modified Rankin thresholds or ordinal approaches used to define favorable outcome, with no increase in mortality. The individual patient data metaanalyses have also demonstrated a strong relationship between onset to treatment time and outcome with the number needed to treat to achieve favorable outcome increasing by approximately 1 for every 20  min delay in treatment initiation.

Guidelines for early management of acute ischemic stroke have been extensively published.²⁸–³² These evidence-based recommendations universally support the use of alteplase in acute ischemic stroke meeting clinical and noncontrast CT brain criteria, who can be treated within 4.5  h of ischemic stroke onset.

Phase 4 Data: Postmarketing Studies in Alteplase Stroke Thrombolysis

There is now a large body of international experience in the use of alteplase in acute ischemic stroke. Many centers have published data allowing perspective on the use of alteplase in routine clinical practice.¹³

The Standard Treatment with Alteplase to Reverse Stroke (STARS) study was a prospective review of the management of stroke with alteplase in 24 academic and 33 community centers.³³ The results from this phase 4 study compared very favorably with those from the NINDS study. The characteristics of the patient population treated with alteplase were similar to those in the NINDS study. The 1-month outcome indicated that 43% were independent and 35% had minimal or no disability. The rate of SICH was low at 3.3% compared with 6.4% in the NINDS study.³³

In Canada, following the approval for the use of alteplase in acute stroke, a national database was required to be established as part of regulatory conditions for approval of alteplase. The Canadian Activase for Stroke Effectiveness study (CASES) was established to collect data prospectively from academic and community hospitals across Canada.³⁴ The results from this database indicate that patients receiving alteplase were older than those in the NINDS cohort with a similar stroke severity. Again the SICH rate was low (4.4%), and the 3-month outcomes were favorable and comparable to the NINDS data.¹³,³⁴ Similar findings have been published from centers in Germany, United States, and Australia.³⁵–³⁷

The safe implementation of treatments in stroke registry began in Europe but has spread internationally.³⁸ These data have provided insights into the effect of age, comorbidities, and risks for symptomatic hemorrhage. With current definitions of symptomatic hemorrhage and eligibility criteria the rate of SICH in real-world practice is <2%.

Although initial postmarketing studies suggested considerable danger in violation of the alteplase stroke protocol, subsequent studies³⁹ have not supported a rigid adherence to NINDS trial criteria. In one early study from Indianapolis, alteplase-related intracranial hemorrhage occurred in 38% of patients with protocol violations, but only in 2% of those patients without protocol violations.⁴⁰ A widely publicized report from Cleveland, largely based at community hospitals, highlighted the problems that can occur.⁴¹ In this cohort of 70 patients from 29 hospitals the rate of SICH, and in-hospital mortality was around 16%. This cohort had the highest reported rate of protocol violations with 50% of patients deviating from national treatment guidelines. A quality improvement program with frequent educational sessions was then initiated to address these problems. A subsequent follow-up report in which stroke alteplase guidelines were adhered to resulted in a significant improvement in outcome at the same group of hospitals.⁴² In contrast, several more recent studies have questioned several of the traditional contraindications to thrombolysis, and a new AHA guideline Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke has been published.⁴³ Factors such as seizure at onset can be circumvented by advanced imaging to prove the diagnosis of stroke. Thrombolysis in pregnancy has not been associated with adverse consequences. Very mild and very severe patients appear to derive similar treatment effect. Even recent bleeding or surgery has become a relative contraindication to be weighed against the consequences of not treating (although the availability of endovascular thrombectomy may reduce the need for such challenging decisions).

Phase 4 data always need to be interpreted with caution as there are often many differences between stroke centers, e.g., university hospitals versus community hospitals, differences in patient demographics, differences in baseline stroke severity, rate of protocol deviations. Adequate and complete follow-up is also very important as is the overall accuracy and degree of completion of database sets.

Future Priorities

Implementation

There are still many challenges to maximize the potential benefits of alteplase in acute stroke. The poor public recognition of stroke symptoms, delays in transportation, and limitations of a 4.5-h time window present considerable obstacles for patient recruitment.⁴⁴ It is estimated that alteplase treatment currently reaches only around 7% of the North American stroke population.⁴⁵ For example, in the NINDS trial, over 17,000 patients were screened, but only 624 eligible subjects were recruited. Most of those excluded were ineligible because of the time that had elapsed since stroke onset. Time delays from stroke onset to presentation continue to be frustrating. Public awareness of the symptoms of stroke is poor and emphasizing the need to act quickly requires considerable education. Studies have shown that one-third of the general public cannot name a single warning sign of stroke.⁴⁴ Prehospital stroke screening tools have been developed (e.g., Los Angeles Prehospital Stroke Scale and the Cincinnati Prehospital Stroke Scale) to facilitate paramedic diagnosis of alteplase eligible stroke patients and prenotification to emergency departments of impending arrival.⁴⁶,⁴⁷

Several institutions have demonstrated marked reductions in door to needle time with reorganization of their systems.⁴⁸–⁵⁰ Emergency department prenotification allows the patient to be met on arrival and transported directly to the CT scanner on the ambulance stretcher. Patient details provided by the ambulance prenotification can be used to preorder the CT scan and obtain medical history details in some cases. These simple, cost-neutral changes have a direct relationship with improved outcomes.⁴⁸

It is agreed that alteplase should only be administered by physicians with expertise in acute stroke with adherence to published treatment guidelines. These may be neurologists or internal medicine or emergency medicine physicians with an interest in stroke. Similarly, nursing protocols, particularly for management of the stroke patient after alteplase, need to be closely followed. Comprehensive registries of alteplase use, including hemorrhage rates, are used in Canada and Europe. Quality assurance via web-based database programs can simplify data collection and allow for more accurate postmarketing surveillance. Web-based programs have also been used to help improve skills in the radiological diagnosis of stroke on CT (e.g., www.neuroimage.co.uk and http://www.aspectsinstroke.com).⁵¹

One innovative approach that has been shown in the prehospital acute neurological therapy and optimization of medical care in stroke patients (PHANTOM-S) randomized trial to both increase alteplase use and speed its administration (by ∼30  min) is the mobile stroke unit with a CT scanner installed in an ambulance.⁵² This approach was pioneered in Germany⁵³ and has now spread to several US and international centers.

Ongoing Trials and Future Directions

Current intravenous thrombolysis strategies are based simply on time from stroke onset. This is a surrogate for the presence of salvageable ischemic penumbra, a zone of incomplete ischemia where neurons are hypoxic and functionally inactive but still viable. The ischemic penumbra is a dynamic, time-based, condition in which brain parenchyma will undergo necrosis over hours to days due to a cascade of biochemical events termed the ischemic cascade.

There are ongoing trials aiming to determine whether alteplase can be used beyond the currently accepted 4.5  h time window, using advanced imaging to identify individual patients with surviving ischemic penumbra (Fig. 1.1), which has been shown to last many hours in some patients.⁵⁴ The EPITHET randomized trial²⁵ and single arm trials such as diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE)⁵⁵ and a study of intravenous thrombolysis with alteplase in MRI-selected patients (MR WITNESS) (NCT01282242) suggest this approach may be safe. Phase 3 clinical trials such as EXTEND²⁶ and ECASS 4:EXTEND⁵⁶ (alteplase vs. placebo 4.5–9  h after stroke onset, including wake-up stroke) are ongoing.

There has been ongoing uncertainty about the optimal dose of alteplase. The dose in most trials was 0.9  mg/kg. However, in Japan 0.6  mg/kg was licensed on the basis of a single-arm study⁵⁷ and concerns about potentially increased risk of intracerebral hemorrhage in Asian populations. The enhanced control of hypertension and thrombolysis stroke study (ENCHANTED) trial⁵⁸ addressed this question. It failed to demonstrate noninferiority of 0.6mg/kg versus 0.9mg/kg alteplase using a margin that was designed to preserve at least 50% of the efficacy of 0.9mg/kg. Although SICH was reduced from 2% to 1% in the low dose group, this came at the expense of a trend towards increased disability. Guidelines have therefore continued to recommend 0.9mg/kg alteplase.

There are also efforts to develop more effective intravenous thrombolytic strategies. Alternative thrombolytic agents include desmoteplase and tenecteplase. Trials of desmoteplase have been repeatedly neutral, confounded by difficulties in identifying the target patient population. Initial studies used visually assessed perfusion imaging but the lack of objective thresholding led to inclusion of many patients with mild perfusion lesions and clinical deficits without a vessel occlusion.⁵⁹ Post hoc analyses demonstrated promising results in those with large mismatch or vessel occlusion.⁶⁰,⁶¹ Subsequent studies used vessel occlusion on noninvasive angiography but there were still a substantial proportion of protocol violations and recanalization was not significantly increased with desmoteplase.⁶²

Tenecteplase is a genetically modified form of tPA, which has greater fibrin specificity and a longer half-life allowing single bolus administration. An initial trial was neutral⁶³ but subsequently an Australian study using lower doses and perfusion imaging selection demonstrated substantial benefits in reperfusion, neurological improvement, and functional outcome.⁶⁴ This has led to the phase 3 tenecteplase versus alteplase for stroke thrombolysis evaluation (TASTE) trial, which has an intended sample size of 1024 patients.

Assisted thrombolysis with transcranial ultrasound sonolysis appeared promising in phase 2 but the phase 3 combined lysis of thrombus with ultrasound and systemic tissue plasminogen activator (tpa) for emergent revascularization in acute ischemic stroke (CLOTBUST-ER) trial was terminated for futility.⁶⁵ Combining alteplase with antiplatelet (eptifibatide) and anticoagulants (argatroban) is also being explored.

Figure 1.1  Imaging the ischemic penumbra with CT perfusion. A patient with left middle cerebral artery occlusion evident as hyperdense artery on (A) thin-slice noncontrast CT with (B) subtle ischemic change confined to the basal ganglia on noncontrast CT. (C) CT angiogram confirming the occlusion and CT perfusion imaging (D) time to maximum (Tmax) map demonstrating delayed flow via leptomeningeal collaterals throughout the left middle cerebral territory. (E) Cerebral blood volume (CBV) and (F) cerebral blood flow (CBF) were relatively preserved indicating a small irreversibly injured ischemic core in the basal ganglia and large ischemic penumbra. (G) Initial angiogram confirmed persistent occlusion despite intravenous alteplase and (H) postthrombectomy revascularization. (I) Diffusion MRI at 24   h after endovascular thrombectomy demonstrated a small infarct in the predicted region and the patient recovered clinically with reduction in NIHSS from 19 to 2.

Endovascular Revascularization Trials

The first phase 3 trial of intraarterial thrombolysis was the prolyse in acute cerebral thromboembolism (PROACT) trial, which used intraarterial thrombolysis, a 6-h time window and focused on patients with MCA-territory infarction, randomized to prourokinase versus placebo.⁶⁶ The trial was positive, but another definitive trial was required by FDA and the drug did not proceed to market.

Early Mechanical Thrombectomy Trials

In 2013 three neutral randomized trials were published. The interventional management of stroke (IMS-3) trial randomized patients to a bridging strategy of intravenous alteplase plus intraarterial treatment with alteplase or a range of early generation devices (Merci, Penumbra, etc.) versus alteplase alone.⁶⁷ Clinical criteria including NIHSS ≥10 and noncontrast CT were used to assess eligibility with no requirement to prove a vessel occlusion as a target for therapy. The trial was stopped early for futility. There were trends to benefit in those with proven arterial occlusion and the very severe group with NIHSS ≥20. The local versus systemic thrombolysis for acute ischemic stroke (SYNTHESIS) trial randomized patients to intravenous versus intraarterial alteplase.⁶⁸ There was a 1-h delay in initiating therapy in the endovascular group and no signal of benefit. The mechanical retrieval and recanalization of stroke clots using embolectomy (MR-RESCUE) trial used a complex form of perfusion imaging analysis in an attempt to identify patients with salvageable brain tissue.⁶⁹ Unfortunately the early generation devices that were used had a poor rate of revascularization. Only 27% achieved reperfusion of >50% of the involved territory (modified treatment in cerebral infarction (mTICI) 2b/3), and no signal of benefit was observed. In addition to the limited device efficacy and