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Optimal Design of Clinical Trials Involving Persons with Disorders of Consciousness

  • Curing Coma Campaign
  • Published:
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Abstract

Background

Limited data exist regarding the optimal clinical trial design for studies involving persons with disorders of consciousness (DoC), and only a few therapies have been tested in high-quality clinical trials. To address this, the Curing Coma Campaign Clinical Trial Working Group performed a gap analysis on the current state of clinical trials in DoC to identify the optimal clinical design for studies involving persons with DoC.

Methods

The Curing Coma Campaign Clinical Trial Working Group was divided into three subgroups to (1) review clinical trials involving persons with DoC, (2) identify unique challenges in the design of clinical trials involving persons with DoC, and (3) recommend optimal clinical trial designs for DoC.

Results

There were 3055 studies screened, and 66 were included in this review. Several knowledge gaps and unique challenges were identified. There is a lack of high-quality clinical trials, and most data regarding patients with DoC are based on observational studies focusing on patients with traumatic brain injury and cardiac arrest. There is a lack of a structured long-term outcome assessment with significant heterogeneity in the methodology, definitions of outcomes, and conduct of studies, especially for long-term follow-up. Another major barrier to conducting clinical trials is the lack of resources, especially in low-income countries. Based on the available data, we recommend incorporating trial designs that use master protocols, sequential multiple assessment randomized trials, and comparative effectiveness research. Adaptive platform trials using a multiarm, multistage approach offer substantial advantages and should make use of biomarkers to assess treatment responses to increase trial efficiency. Finally, sound infrastructure and international collaboration are essential to facilitate the conduct of trials in patients with DoC.

Conclusions

Conduct of trials in patients with DoC should make use of master protocols and adaptive design and establish international registries incorporating standardized assessment tools. This will allow the establishment of evidence-based practice recommendations and decrease variations in care.

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Fig. 1

Reproduced from Park et al. [28]

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Source of Support

S-MC is funded by National Heart, Lung, and Blood Institute grant 1K23HL157610.

References

  1. Provencio JJ, Hemphill JC, Claassen J, et al. The curing coma campaign: framing initial scientific challenges-proceedings of the first curing coma campaign scientific advisory council meeting. Neurocrit Care. 2020;33(1):1–12. https://doi.org/10.1007/s12028-020-01028-9.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Mainali S, Aiyagari V, Alexander S, et al. Proceedings of the second curing coma campaign nih symposium: challenging the future of research for coma and disorders of consciousness. Neurocrit Care. 2022;37(1):326–50. https://doi.org/10.1007/s12028-022-01505-3.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Edlow BL, Sanz LRD, Polizzotto L, et al. Therapies to restore consciousness in patients with severe brain injuries: a gap analysis and future directions. Neurocrit Care. 2021;35(Suppl 1):68–85. https://doi.org/10.1007/s12028-021-01227-y.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):1000097. https://doi.org/10.1371/journal.pmed.1000097.

    Article  Google Scholar 

  5. Helbok R, Rass V, Beghi E, et al. The curing coma campaign international survey on coma epidemiology, evaluation, and therapy (Come Together). Neurocrit Care. 2022;37(1):47–59. https://doi.org/10.1007/s12028-021-01425-8.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Giacino JT, Whyte J, Bagiella E, et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med. 2012;366(9):819–26. https://doi.org/10.1056/NEJMoa1102609.

    Article  CAS  PubMed  Google Scholar 

  7. Berry DA. Emerging innovations in clinical trial design. Clin Pharmacol Ther. 2016;99(1):82–91. https://doi.org/10.1002/cpt.285.

    Article  CAS  PubMed  Google Scholar 

  8. Cinnella G. Enrolling patients into multiple trials: it is time for glasnost*. Crit Care Med. 2015;43(2):485–6. https://doi.org/10.1097/CCM.0000000000000756.

    Article  PubMed  Google Scholar 

  9. Gertner E. COVID-19 trial co-enrolment and subsequent enrolment. Lancet. 2020;396(10249):461–2. https://doi.org/10.1016/S0140-6736(20)31537-3.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Vanderbeek AM, Bliss JM, Yin Z, Yap C. Implementation of platform trials in the COVID-19 pandemic: a rapid review. Contemp Clin Trials. 2022;112:106625. https://doi.org/10.1016/j.cct.2021.106625.

    Article  PubMed  Google Scholar 

  11. Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. 2017;377(1):62–70. https://doi.org/10.1056/NEJMra1510062.

    Article  CAS  PubMed  Google Scholar 

  12. Wallace M, Moodie EEM, Stephens DA. SMART thinking: a review of recent developments in sequential multiple assignment randomized trials. Curr Epidemiol Rep. 2016;3:225–32.

    Article  Google Scholar 

  13. Williams CM, Skinner EH, James AM, Cook JL, McPhail SM, Haines TP. Comparative effectiveness research for the clinician researcher: a framework for making a methodological design choice. Trials. 2016;17(1):406. https://doi.org/10.1186/s13063-016-1535-6.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kowalski RG, Hammond FM, Weintraub AH, et al. Recovery of consciousness and functional outcome in moderate and severe traumatic brain injury. JAMA Neurol. 2021;78(5):548–57. https://doi.org/10.1001/jamaneurol.2021.0084.

    Article  PubMed  Google Scholar 

  15. Hocker S, Shah S, Vespa P, et al. The future of neurocritical care research: proceedings and recommendations from the fifth neurocritical care research network conference. Neurocrit Care. 2020;32(1):311–6. https://doi.org/10.1007/s12028-019-00767-8.

    Article  CAS  PubMed  Google Scholar 

  16. Suarez JI, Geocadin R, Hall C, et al. The neurocritical care research network: NCRN. Neurocrit Care. 2012;16(1):29–34. https://doi.org/10.1007/s12028-011-9612-x.

    Article  CAS  PubMed  Google Scholar 

  17. Claassen J, Akbari Y, Alexander S, et al. Proceedings of the first curing coma campaign NIH symposium: challenging the future of research for coma and disorders of consciousness. Neurocrit Care. 2021;35(Suppl 1):4–23. https://doi.org/10.1007/s12028-021-01260-x.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Olson DM, Hemphill JC, Provencio JJ, et al. The curing coma campaign and the future of coma research. Semin Neurol. 2022;42(3):393–402. https://doi.org/10.1055/a-1887-7104.

    Article  PubMed  Google Scholar 

  19. Hill KD, Kannankeril PJ, Jacobs JP, et al. Methylprednisolone for heart surgery in infants—a randomized. Controlled Trial N Engl J Med. 2022;387(23):2138–49. https://doi.org/10.1056/NEJMoa2212667.

    Article  CAS  PubMed  Google Scholar 

  20. Lee B, Gately L, Lok SW, et al. Leveraging comprehensive cancer registry data to enable a broad range of research, audit and patient support activities. Cancers (Basel). 2022. https://doi.org/10.3390/cancers14174131.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lewis A, Young MJ, Rohaut B, et al. Ethics along the continuum of research involving persons with disorders of consciousness. Neurocrit Care. 2023. https://doi.org/10.1007/s12028-023-01708-2.

    Article  PubMed  Google Scholar 

  22. Del Álamo M, Bührer C, Fisher D, et al. Identifying obstacles hindering the conduct of academic-sponsored trials for drug repurposing on rare-diseases: an analysis of six use cases. Trials. 2022;23(1):783. https://doi.org/10.1186/s13063-022-06713-y.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hakoum MB, Jouni N, Abou-Jaoude EA, et al. Characteristics of funding of clinical trials: cross-sectional survey and proposed guidance. BMJ Open. 2017;7(10):e015997. https://doi.org/10.1136/bmjopen-2017-015997.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sismondo S. Epistemic corruption, the pharmaceutical industry, and the body of medical science. Front Res Metr Anal. 2021;6:614013. https://doi.org/10.3389/frma.2021.614013.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hudson KL, Lauer MS, Collins FS. Toward a new era of trust and transparency in clinical trials. JAMA. 2016;316(13):1353–4. https://doi.org/10.1001/jama.2016.14668.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Roustit M, Demarcq O, Laporte S, et al. Therapie. 2023;78(1):19–28. https://doi.org/10.1016/j.therap.2022.11.011.

    Article  PubMed  Google Scholar 

  27. Mott M, Janis S, Koroshetz WJ. StrokeNet takes off: national institute of neurological disorders and stroke organizational update. Stroke. 2016;47(3):e51–2. https://doi.org/10.1161/STROKEAHA.115.012063.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Park JJH, Siden E, Zoratti MJ, et al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials. 2019;20(1):572. https://doi.org/10.1186/s13063-019-3664-1.

    Article  PubMed  PubMed Central  Google Scholar 

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Author information

Author notes

  1. Sung-Min Cho and Chiara Robba have contributed equally as first authors.

Authors and Affiliations

  1. Neuroscience Critical Care Division, Departments of Neurology, and Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe Street , Baltimore, MD, 21287, USA

    Sung-Min Cho, Daniel F. Hanley, Robert D. Stevens, Wendy C. Ziai, Marcus Spann & Jose I. Suarez

  2. IRCCS for Oncology and Neuroscience and Department of Surgical Science and Integrated Diagnostic, San Martino Policlinico Hospital, University of Genoa, Genoa, Italy

    Chiara Robba

  3. Departments of Neurology, Washington University in St. Louis, St. Louis, MO, USA

    Michael N. Diringer

  4. Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA

    J. Claude Hemphill

  5. University of Amsterdam, Amsterdam, Netherlands

    Janneke Horn

  6. Division of Neurocritical Care, Department of Neurology and Neurosurgery, New York University, New York, NY, USA

    Ariane Lewis

  7. Department of Adult Health and Gerontological Nursing, College of Nursing, Rush University, Chicago, IL, USA

    Sarah L. Livesay

  8. Department of Medicine, University of Cambridge, Cambridge, UK

    David Menon

  9. Departments of Neurology and Intensive Care Medicine, Paris-Descartes University, Paris, France

    Tarek Sharshar

  10. Department of Epidemiology, University of Iowa, Iowa City, IA, USA

    James Torner

  11. Departments of Neurology and Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA

    Paul M. Vespa

  12. Departments of Neurology and Medicine, Innsbruck Medical University, Innsbruck, Austria

    Raimund Helbok

Authors
  1. Sung-Min Cho
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  2. Chiara Robba
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Curing Coma Campaign and its contributing members

Contributions

S-MC, CR, and JIS wrote the initial draft of the manuscript. S-MC and CR contributed equally as first authors. All coauthors edited the manuscript and approved the final content.

Corresponding author

Correspondence to Jose I. Suarez.

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Cho, SM., Robba, C., Diringer, M.N. et al. Optimal Design of Clinical Trials Involving Persons with Disorders of Consciousness. Neurocrit Care 40, 74–80 (2024). https://doi.org/10.1007/s12028-023-01813-2

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