Clinical trial NCT03814356: Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness
Official title: Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness - A Phase 1 Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Brain Injury Traumatic Severe (Diagnosis)
Coma
Consciousness, Level Altered
Anoxic Brain Injury
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
First posted: 2019-01-24
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years
2. Severe, acute traumatic brain injury
3. Diagnosis of Coma, Vegetative State, or Minimally Conscious State

Exclusion Criteria:

1. Penetrating brain injury caused by a metallic missile/object (e.g. bullet)
2. Body metal contraindicating MRI
3. Prisoner or ward of the state
4. Neurological

   1. Bilateral dilated unresponsive pupils
   2. 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)
   3. Intracranial bolt
   4. Status epilepticus or concern for post-ictal state
5. Cardiovascular

   1. Poorly controlled hypertension (SBP \> 200 mmHg of DBP \> 120mmHg for 30 minutes, despite anti-hypertensive therapy, within the past 24 hours)
   2. Coronary artery disease
   3. ST elevation myocardial infarction
   4. Acute coronary syndrome
   5. Hemodynamically significant dysrhythmia
   6. Congestive heart failure
   7. Cardiomyopathy (including Takotsubo cardiomyopathy)
   8. Other severe structural cardiac abnormalities
6. Renal

   a. Renal failure requiring renal replacement therapy (e.g. CVVH or HD)
7. Endocrine

   a. History of or clinical suspicion for thyrotoxicosis
8. Reproductive

   a. Pregnancy
9. Ophthalmologic

   a. History of glaucoma
10. Pharmacologic

    a. Monoamine oxidase inhibitor therapy within past 14 days
11. Other

    1. 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

Primary outcomes:
measure: Adverse Events
timeFrame: 4 Days
Secondary outcomes:
measure: Maximal Serum Concentration
timeFrame: 4 Days
measure: Serum Half-life
timeFrame: 4 Days
measure: Cerebral Cortical Connectivity as Measured by fMRI
timeFrame: 4 Days
measure: Cerebral Cortical Connectivity as Measured by EEG
timeFrame: 4 Days
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Brian L Edlow, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Edlow BL, Barra ME, Zhou DW, Foulkes AS, Snider SB, Threlkeld ZD, Chakravarty S, Kirsch JE, Chan ST, Meisler SL, Bleck TP, Fins JJ, Giacino JT, Hochberg LR, Solt K, Brown EN, Bodien YG. Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit. Neurocrit Care. 2020 Oct;33(2):364-375. doi: 10.1007/s12028-020-01062-7. Epub 2020 Aug 13.