Anoxic Brain Injury, Brain Injury Traumatic Severe (Diagnosis), Coma, Consciousness, Level Altered
Conditions
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.
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.
Interventions
DRUGMethylphenidate
IV MPH
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events at Each Dose | 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
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximal Serum Concentration of IV Methylphenidate (MPH) | 4 Days | The median (range) time (hours) to maximum concentrations at 0.5, 1.0, and 2.0 mg/kg doses was measured. |
| Serum Half-life of IV Methylphenidate (MPH) | 4 Days | The mean (SD) serum half-lives (hours) at 0.5, 1.0, and 2.0 mg/kg doses was assessed. |
| Cerebral Cortical Connectivity as Measured by fMRI | 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. |
| Cerebral Cortical Connectivity as Measured by EEG | 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. |
Countries
United States
Participant flow
Pre-assignment details
10 patients were enrolled with informed consent provided by surrogate decision-makers, but one patient was withdrawn from the study by surrogate decision-makers prior to any study procedures were performed.
Participants by arm
| Arm | Count |
|---|---|
| IV MPH 9 patients with severe traumatic brain injury (TBI), age range 25-77, all male. | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | IV MPH |
|---|---|
| Age, Continuous | 49.3 years STANDARD_DEVIATION 21.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 | 0 / 6 |
| other Total, other adverse events | 0 / 9 | 2 / 9 | 1 / 6 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 | 0 / 6 |
Outcome results
Primary
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
Population: 9 participants received the 0.5 mg/kg IV MPH dose and and the 1.0 mg/kg IV MPH dose. 6 participants received the 2.0 mg/kg IV MPH dose.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IV MPH | Number of Participants With Adverse Events at Each Dose | 0.5 mg/kg IV MPH | 0 Participants |
| IV MPH | Number of Participants With Adverse Events at Each Dose | 1.0 mg/kg IV MPH | 2 Participants |
| IV MPH | Number of Participants With Adverse Events at Each Dose | 2.0 mg/kg IV MPH | 1 Participants |
Secondary
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
Population: EEG data were obtained in all nine study participants at the 0.5 mg/kg dose and 1.0 mg/kg dose, and in 6 participants at the 2.0 mg/kg dose.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IV MPH | Cerebral Cortical Connectivity as Measured by EEG | 0.5 mg/kg IV MPH | 4 number of responders |
| IV MPH | Cerebral Cortical Connectivity as Measured by EEG | 1.0 mg/kg IV MPH | 2 number of responders |
| IV MPH | Cerebral Cortical Connectivity as Measured by EEG | 2.0 mg/kg IV MPH | 0 number of responders |
Secondary
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
Population: Functional MRI data were obtained in two study participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IV MPH | Cerebral Cortical Connectivity as Measured by fMRI | 1 number of responders |
Secondary
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
Population: The mean (SD) serum half-lives (hours) at 0.5, 1.0, and 2.0 mg/kg doses was assessed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IV MPH | Serum Half-life of IV Methylphenidate (MPH) | 0.5 mg/kg | 5.07 hours | Standard Deviation 2.55 |
| IV MPH | Serum Half-life of IV Methylphenidate (MPH) | 1.0 mg/kg | 4.39 hours | Standard Deviation 1.92 |
| IV MPH | Serum Half-life of IV Methylphenidate (MPH) | 2.0 mg/kg | 5.01 hours | Standard Deviation 1.8 |
Secondary
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
Population: We measured the median (range) time (hours) to maximum concentrations at 0.5, 1.0, and 2.0 mg/kg doses of IV MPH.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IV MPH | Time to Maximal Serum Concentration of IV Methylphenidate (MPH) | 0.5 mg/kg IV MPH | 0.12 hours |
| IV MPH | Time to Maximal Serum Concentration of IV Methylphenidate (MPH) | 1.0 mg/kg IV MPH | 0.15 hours |
| IV MPH | Time to Maximal Serum Concentration of IV Methylphenidate (MPH) | 2.0 mg/kg IV MPH | 0.23 hours |