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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Coma; Anoxic Brain Injury; Consciousness, Level Altered; Brain Injury Traumatic Severe (Diagnosis)
• Intervention / Treatment: Drug: Methylphenidate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events at Each Dose	Adverse Events An AE is defined as any untoward medical occurrence associated with the use of an intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). In the STIMPACT Trial an AE may include, but is not limited to: Sustained hypertension = SBP > 200 mmHg or DBP > 120 mmHg for > 30 min, refractory to medical therapy, or; Sustained tachycardia = HR > 120 bpm for > 30 min, refractory to medical therapy, or; Sustained intracranial hypertension = ICP > 25 mmHg for > 5 min, refractory to medical therapy Serious Adverse Events An AE or suspected adverse reaction is considered "serious" if, in the view of the investigator or the Independent Medical Monitor, it results in any of the following outcomes: Death not related to withdrawal of life-sustaining therapy; A life-threatening event; Prolongation of existing hospitalization; Significant incapacity or substantial disruption of the ability to conduct normal life function	4 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Maximal Serum Concentration of IV Methylphenidate (MPH)	The median (range) time (hours) to maximum concentrations at 0.5, 1.0, and 2.0 mg/kg doses was measured.	4 Days
Serum Half-life of IV Methylphenidate (MPH)	The mean (SD) serum half-lives (hours) at 0.5, 1.0, and 2.0 mg/kg doses was assessed.	4 Days
Cerebral Cortical Connectivity as Measured by fMRI	We performed a change-point analysis of time-series resting-state fMRI data to determine if individual participants responded to the 2.0 mg/kg dose of IV MPH. Specifically, we measured resting-state fMRI connectivity between the brainstem ventral tegmental area and the default mode network after the bolus of IV MPH as compared to before the bolus of IV MPH. The bolus of IV MPH was administered in the MRI scanner while the patient was undergoing a 40-minute resting-state fMRI (10 minutes of data acquisition pre-bolus, 30 minutes of data acquisition post-bolus). The goal of the analysis was to determine if each patient responded to IV MPH, as defined by a positive change point (i.e., increase in connectivity after the bolus of IV MPH). Connectivity was measured via Pearson correlations using the software package CONN.	4 Days
Cerebral Cortical Connectivity as Measured by EEG	We performed a change-point analysis of time-series resting-state EEG data to determine if individual participants responded to each dose of IV MPH. Specifically, we measured resting-state EEG background rhythm, using the alpha/delta ratio as a quantitative biomarker of overall brain function (i.e., alpha/delta ratio was measured for all EEG leads in a clinical 19-electrode montage). In a continuous time-series analysis of resting EEG data acquired 1 hour before and 1 hour after each IV MPH bolus, we tested for a "change-point" in the alpha/delta ratio, which represents a statistically significant increase in alpha/delta ratio. The goal of the analysis was to determine if each patient responded to IV MPH, as defined by a positive change point (i.e., increase in alpha/delta after the bolus of IV MPH). EEG analyses were performed using MATLAB software.	4 Days

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Brian L Edlow, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• 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.

Helpful Links

• Homepage of the Laboratory for NeuroImaging of Coma and Consciousness

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2020
• Primary Completion (Actual): April 1, 2024
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: January 15, 2019
• First Submitted That Met QC Criteria: January 18, 2019
• First Posted (Actual): January 24, 2019

Study Record Updates

• Last Update Posted (Estimated): October 29, 2025
• Last Update Submitted That Met QC Criteria: October 15, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Mental Disorders; Pathologic Processes; Neurobehavioral Manifestations; Neurocognitive Disorders; Brain Ischemia; Signs and Symptoms, Respiratory; Hypoxia, Brain; Unconsciousness; Hypoxia; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Disease; Hypoxia-Ischemia, Brain; Consciousness Disorders; Coma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Carboxylic Acids; Piperidines; Acids, Carbocyclic; Phenylacetates; Methylphenidate; 5,10-dihydro-5-methylphenazine
• Other Study ID Numbers: 140675; DP2HD101400 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No