Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit.
Biomarker
Brain injury
Clinical trial
Coma
Connectome
Consciousness
Journal
Neurocritical care
ISSN: 1556-0961
Titre abrégé: Neurocrit Care
Pays: United States
ID NLM: 101156086
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
02
12
2019
accepted:
18
04
2020
pubmed:
15
8
2020
medline:
30
9
2021
entrez:
15
8
2020
Statut:
ppublish
Résumé
There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network (ClinicalTrials.gov NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5-2.0 mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug's pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.
Identifiants
pubmed: 32794142
doi: 10.1007/s12028-020-01062-7
pii: 10.1007/s12028-020-01062-7
pmc: PMC8336723
mid: NIHMS1620387
doi:
Banques de données
ClinicalTrials.gov
['NCT03814356']
Types de publication
Clinical Trial Protocol
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
364-375Subventions
Organisme : NINDS NIH HHS
ID : K23 NS094538
Pays : United States
Organisme : NINDS NIH HHS
ID : R25 NS088248
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002541
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS109627
Pays : United States
Organisme : NINDS NIH HHS
ID : RF1 NS115268
Pays : United States
Organisme : NICHD NIH HHS
ID : DP2 HD101400
Pays : United States
Commentaires et corrections
Type : CommentIn
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