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

Sponsor

Massachusetts General Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT03814356

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Brain Injury Traumatic Severe (Diagnosis) Coma Consciousness, Level Altered Anoxic Brain Injury	Drug: Methylphenidate	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

22 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 24, 2020

Anticipated Primary Completion Date :

Feb 23, 2024

Anticipated Study Completion Date :

Feb 23, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IV MPH 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 IV MPH Other Names: MPH

Arm

Intervention/Treatment

Experimental: IV MPH

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

IV MPH

Other Names:

MPH

Outcome Measures

Primary Outcome Measures

Adverse Events [4 Days]
The number of drug-related adverse events at each dose of IV MPH

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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

Endocrine

History of or clinical suspicion for thyrotoxicosis

Reproductive

Pregnancy

Ophthalmologic

History of glaucoma

Pharmacologic

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