A Phase 1 interventional study of Methylphenidate in Brain Injury Traumatic Severe (Diagnosis), Coma and Consciousness, Level Altered, sponsored by Massachusetts General Hospital. Active, not recruiting at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-10-29.
Sponsored by Massachusetts General Hospital · Phase 1, Interventional, and Treatment
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.
138 studies on the registry are indexed under Coma; 35 are open to participants now.
This study's enrollment of 10 is below the median of 85 across 77 interventional studies indexed under Coma.
Browse Coma studies →Massachusetts General Hospital is the lead sponsor of 2,586 studies on the registry; 447 are open to participants now.
Of its 222 completed or terminated interventional studies of FDA-regulated products, 168 (76%) have results posted.
Compared within Coma, this study's primary condition as ClinicalTrials.gg classifies it; the registry's first condition term is Disease. The counts are of registry records indexed under each term, refreshed daily. How we classify →
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Exclusion Criteria:
Neurological
Cardiovascular
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
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
Also known as: MPH
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
Time frame: 4 Days
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 4 Days
| Milestone | IV MPH |
|---|---|
| Started | 9 |
| Completed | 9 |
| Not completed | 0 |
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
| Participants | IV MPH |
|---|---|
| 0.5 mg/kg IV MPH | 0 |
| 1.0 mg/kg IV MPH | 2 |
| 2.0 mg/kg IV MPH | 1 |
The median (range) time (hours) to maximum concentrations at 0.5, 1.0, and 2.0 mg/kg doses was measured.
| hours | IV MPH |
|---|---|
| 0.5 mg/kg IV MPH | 0.12 (0.08 to 0.13) |
| 1.0 mg/kg IV MPH | 0.15 (0.07 to 0.18) |
| 2.0 mg/kg IV MPH | 0.23 (0.2 to 0.3) |
The mean (SD) serum half-lives (hours) at 0.5, 1.0, and 2.0 mg/kg doses was assessed.
| hours | IV MPH |
|---|---|
| 0.5 mg/kg | 5.07 ± 2.55 |
| 1.0 mg/kg | 4.39 ± 1.92 |
| 2.0 mg/kg | 5.01 ± 1.80 |
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.
| number of responders | IV MPH |
|---|---|
| Cerebral Cortical Connectivity as Measured by fMRI | 1 |
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.
| number of responders | IV MPH |
|---|---|
| 0.5 mg/kg IV MPH | 4 |
| 1.0 mg/kg IV MPH | 2 |
| 2.0 mg/kg IV MPH | 0 |
Collected over 4 days. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| 0.5 mg/kg IV MPH | 0/9 (0%) | 0/9 (0%) | 0/9 (0%) |
| 1.0 mg/kg IV MPH | 0/9 (0%) | 0/9 (0%) | 2/9 (22.2%) |
| 2.0 mg/kg IV MPH | 0/6 (0%) | 0/6 (0%) | 1/6 (16.7%) |
| Event | 0.5 mg/kg IV MPH | 1.0 mg/kg IV MPH | 2.0 mg/kg IV MPH |
|---|---|---|---|
| Transaminitis (increased ALT/AST)Hepatobiliary disorders | 0/9 | 0/9 | 1/6 |
| Paroxysmal Sympathetic HyperactivityNervous system disorders | 0/9 | 1/9 | 0/6 |
| InsomniaNervous system disorders | 0/9 | 1/9 | 0/6 |
| EmesisGastrointestinal disorders | 0/9 | 1/9 | 0/6 |
adults with severe TBI
| Age, Continuous(years) | IV MPH |
|---|---|
| Mean | 49.3 ± 21.3 |
| Sex: Female, Male(Participants) | IV MPH |
|---|---|
| Female | 0 |
| Male | 9 |
| Ethnicity (NIH/OMB)(Participants) | IV MPH |
|---|---|
| Hispanic or Latino | 1 |
| Not Hispanic or Latino | 8 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | IV MPH |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 2 |
| White | 6 |
| More than one race | 0 |
| Unknown or Not Reported | 1 |
PDFs hosted by the registry, ClinicalTrials.gov.
Ran from Aug 2020 to primary completion in Apr 2024, 43 months.
Results were first posted in Oct 2025, 1 year 6 months after primary completion.
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Studies of the drug tested here: Methylphenidate
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