Key design elements of successful acute ischemic stroke treatment trials

L Yperzeele; A Shoamanesh; Y V Venugopalan; S Chapman; M V Mazya; M Charalambous; V Caso; W Hacke; P M Bath; I Koltsov

doi:10.1186/s42466-022-00221-9

Key design elements of successful acute ischemic stroke treatment trials

Neurol Res Pract. 2023 Jan 5;5(1):1. doi: 10.1186/s42466-022-00221-9.

Authors

L Yperzeele^{1

2}, A Shoamanesh³, Y V Venugopalan⁴, S Chapman⁵, M V Mazya^{6

7}, M Charalambous^{8

9}, V Caso¹⁰, W Hacke¹¹, P M Bath¹², I Koltsov^{13

14

15}

Affiliations

¹ Antwerp NeuroVascular Center and Stroke Unit, Department of Neurology, University Hospital Antwerp, Edegem, Belgium.
² Translational Neurosciences Research Group, Faculty of Medicine and Health Sciences, University of Antwerp, Edegem, Belgium.
³ Division of Neurology, McMaster University / Population Health Research Institute, Hamilton, Canada.
⁴ Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.
⁵ Department of Neurology, University of Virginia, Charlottesville, USA.
⁶ Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
⁷ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁸ Department of Rehabilitation Sciences, Cyprus University of Technology, Limassol, Cyprus.
⁹ Laboratory of Cognitive and Neurological Sciences, Neurology Unit, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
¹⁰ Stroke Unit, Santa Maria Della Misericordia Hospital, University of Perugia, Perugia, Italy.
¹¹ Department of Neurology, Ruprechts Karl University, Heidelberg, Germany. werner.hacke@med.uni-heidelberg.de.
¹² Stroke Trials Unit, Mental Health & Clinical Neuroscience, University of Nottingham, Nottingham, UK.
¹³ Cerebrovascular Diseases Laboratory, Pirogov Russian National Research Medical University, Moscow, Russia.
¹⁴ Neurology, Neurosurgery, and Medical Genetics Department, Pirogov Russian National Research Medical University, Moscow, Russia.
¹⁵ Neuroimmunology Department, Federal Center of Brain Research and Neurotechnologies, Moscow, Russia.

Abstract

Purpose: We review key design elements of positive randomized controlled trials (RCTs) in acute ischemic stroke (AIS) treatment and summarize their main characteristics.

Method: We searched Medline, Pubmed and Cochrane databases for positive RCTs in AIS treatment. Trials were included if (1) they had a randomized controlled design, with (at least partial) blinding for endpoints, (2) they tested against placebo (or on top of standard therapy in a superiority design) or against approved therapy; (3) the protocol was registered and/or published before trial termination and unblinding (if required at study commencement); (4) the primary endpoint was positive in the intention to treat analysis; and (5) the study findings led to approval of the investigational product and/or high ranked recommendations. A topical approach was used, therefore the findings were summarized as a narrative review.

Findings: Seventeen positive RCTs met the inclusion criteria. The majority of trials included less than 1000 patients (n = 15), had highly selective inclusion criteria (n = 16), used the modified Rankin score as a primary endpoint (n = 15) and had a frequentist design (n = 16). Trials tended to be national (n = 12), investigator-initiated and performed with public funding (n = 11).

Discussion: Smaller but selective trials are useful to identify efficacy in a particular subgroup of stroke patients. It may also be of advantage to limit the number of participating countries and centers to avoid heterogeneity in stroke management and bureaucratic burden.

Conclusion: The key characteristics of positive RCTs in AIS treatment described here may assist in the design of further trials investigating a single intervention with a potentially high effect size.

Keywords: Acute stroke care; Acute stroke therapy; Randomized controlled trials; Stroke; Stroke research; Trial design.

Publication types

Review