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Active, Not Recruiting

NCT Number: NCT03814356

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

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.

Active, Not Recruiting

This study is active but is not currently recruiting participants.

Key information

Conditions

Brain Injury Traumatic Severe (Diagnosis) Anoxic Brain Injury Brain Diseases Brain Ischemia Cardiovascular Diseases Central Nervous System Diseases Cerebrovascular Disorders Coma Consciousness Disorders Consciousness, Level Altered Disease Hypoxia Hypoxia, Brain Hypoxia-Ischemia, Brain Mental Disorders Nervous System Diseases Neurobehavioral Manifestations Neurocognitive Disorders Neurologic Manifestations Pathologic Processes Pathological Conditions, Signs and Symptoms Signs and Symptoms Signs and Symptoms, Respiratory Unconsciousness Vascular Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Methylphenidate

Drug

IV MPH

Other names: MPH

Primary outcomes

  1. Number of Participants With Adverse Events at Each Dose

    Time frame: 4 Days

    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

Secondary outcomes

  1. Time to Maximal Serum Concentration of IV Methylphenidate (MPH)

    Time frame: 4 Days

    The median (range) time (hours) to maximum concentrations at 0.5, 1.0, and 2.0 mg/kg doses was measured.

  2. Serum Half-life of IV Methylphenidate (MPH)

    Time frame: 4 Days

    The mean (SD) serum half-lives (hours) at 0.5, 1.0, and 2.0 mg/kg doses was assessed.

  3. Cerebral Cortical Connectivity as Measured by fMRI

    Time frame: 4 Days

    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. Cerebral Cortical Connectivity as Measured by EEG

    Time frame: 4 Days

    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.

Sponsors and collaborators

Lead sponsor

Massachusetts General Hospital

Other

Collaborators

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Registry information

Official study title

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

Acronym: STIMPACT

Important dates

Study start
2020
Primary completion
2024
Study completion
2026
First posted
Jan 24, 2019
Registry last updated
Oct 29, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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