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

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.

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

We measured the median (range) time (hours) to maximum concentrations at 0.5, 1.0, and 2.0 mg/kg doses of IV MPH.

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

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

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.

Functional MRI data were obtained in two study participants.

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.

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.