Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness

Study Overview
=================
Brief Summary
-----------------
Phase 1 of the STIMPACT trial is an open label,dose-escalation,safety study of intravenous (IV) methylphenidate (MPH) therapy in patients with disorders of consciousness (DoC) caused by severe brain injuries. To be classified as having a DoC, a patient must be in a coma, vegetative state (VS), or minimally conscious state (MCS), as determined by behavioral assessment using the Coma Recovery Scale-Revised (CRS-R). Patients with DoC admitted to the intensive care unit (ICU) will be eligible for the study. A total of 10 patients with DoC will be enrolled in the Phase 1 study. Patients will receive escalating daily doses of IV MPH starting at 0.5 mg/kg, increasing stepwise to 1.0mg/kg and 2.0 mg/kg unless an adverse event (AE) necessitates dose de-escalation or a serious adverse event (SAE) necessitates that the patient stop participation in the study. Pharmacokinetics will be evaluated in selected patients with indwelling venous catheters or arterial catheters via serial serum measurements of MPH at each dose. The pharmacodynamic properties of IV MPH at each dose will be assessed by comparison of pre-versus post-dose EEG-based measures. The pharmacodynamic properties of the maximum tolerated dose will also be assessed by comparison of pre-versus post-dose resting state functional MRI (rs-fMRI) connectivity measures. Finally, we will test the association between structural connectivity of the ventral tegmental area (VTA), a dopaminergic brainstem nucleus that is believed to mediate MPH activation of the cerebral cortex, and EEG and rs-fMRI pharmacodynamic measures.

Official Title
-----------------
Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness - A Phase 1 Study

Conditions
-----------------
Coma, Anoxic Brain Injury, Brain Injury Traumatic Severe (Diagnosis), Consciousness, Level Altered

Intervention / Treatment
-----------------
* Drug: Methylphenidate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years Severe, acute traumatic brain injury Diagnosis of Coma, Vegetative State, or Minimally Conscious State Exclusion Criteria: Penetrating brain injury caused by a metallic missile/object (e.g. bullet) Body metal contraindicating MRI Prisoner or ward of the state Neurological Bilateral dilated unresponsive pupils Intracranial hypertension (Intracranial Pressure [ICP] > 25 mmHg for > 5 min within past 24 hours with head-of-bed at standard clinical angle of 30-45 degrees) Intracranial bolt Status epilepticus or concern for post-ictal state Cardiovascular Poorly controlled hypertension (SBP > 200 mmHg of DBP > 120mmHg for 30 minutes, despite anti-hypertensive therapy, within the past 24 hours) Coronary artery disease ST elevation myocardial infarction Acute coronary syndrome Hemodynamically significant dysrhythmia Congestive heart failure Cardiomyopathy (including Takotsubo cardiomyopathy) Other severe structural cardiac abnormalities Renal a. Renal failure requiring renal replacement therapy (e.g. CVVH or HD) Endocrine a. History of or clinical suspicion for thyrotoxicosis Reproductive a. Pregnancy Ophthalmologic a. History of glaucoma Pharmacologic a. Monoamine oxidase inhibitor therapy within past 14 days Other Any condition or finding that in the judgment of the PI or treating clinical team significantly increases the risk or significantly decreases the likelihood of a response to IV MPH

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV MPH<br>All patients will receive IV Methylphenidate (MPH). Patients will receive escalating daily doses of IV MPH starting at 0.5 mg/kg, increasing stepwise to 1.0mg/kg and 2.0 mg/kg unless an adverse event (AE) necessitates dose de-escalation or a serious adverse event (SAE) necessitates that the patient stop participation in the study. | Drug: Methylphenidate<br>* IV MPH<br>* Other names: MPH;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | The number of drug-related adverse events at each dose of IV MPH | 4 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Serum Concentration | The time to maximal serum concentration at each dose of IV MPH | 4 Days | 
| Serum Half-life | Serum half-life of IV MPH at each dose of IV MPH | 4 Days | 
| Cerebral Cortical Connectivity as Measured by fMRI | The effect of the maximum tolerated of IV MPH dose on brain connectivity, as measured by resting state fMRI | 4 Days | 
| Cerebral Cortical Connectivity as Measured by EEG | The effect of each of IV MPH dose on cerebral cortical connectivity, as measured by EEG | 4 Days |