• Brian L Edlow, Leandro R D Sanz, Len Polizzotto, Nader Pouratian, John D Rolston, Samuel B Snider, Aurore Thibaut, Robert D Stevens, Olivia Gosseries, and Curing Coma Campaign and its contributing members.
• Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 175 Cambridge Street - Suite 300, Boston, MA, 02114, USA. bedlow@mgh.harvard.edu.
• Neurocrit Care. 2021 Jul 1; 35 (Suppl 1): 68-85.

Background/ObjectiveFor patients with disorders of consciousness (DoC) and their families, the search for new therapies has been a source of hope and frustration. Almost all clinical trials in patients with DoC have been limited by small sample sizes, lack of placebo groups, and use of heterogeneous outcome measures. As a result, few therapies have strong evidence to support their use; amantadine is the only therapy recommended by current clinical guidelines, specifically for patients with DoC caused by severe traumatic brain injury. To foster and advance development of consciousness-promoting therapies for patients with DoC, the Curing Coma Campaign convened a Coma Science Work Group to perform a gap analysis.MethodsWe consider five classes of therapies: (1) pharmacologic; (2) electromagnetic; (3) mechanical; (4) sensory; and (5) regenerative. For each class of therapy, we summarize the state of the science, identify gaps in knowledge, and suggest future directions for therapy development.ResultsKnowledge gaps in all five therapeutic classes can be attributed to the lack of: (1) a unifying conceptual framework for evaluating therapeutic mechanisms of action; (2) large-scale randomized controlled trials; and (3) pharmacodynamic biomarkers that measure subclinical therapeutic effects in early-phase trials. To address these gaps, we propose a precision medicine approach in which clinical trials selectively enroll patients based upon their physiological receptivity to targeted therapies, and therapeutic effects are measured by complementary behavioral, neuroimaging, and electrophysiologic endpoints.ConclusionsThis personalized approach can be realized through rigorous clinical trial design and international collaboration, both of which will be essential for advancing the development of new therapies and ultimately improving the lives of patients with DoC.

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