Bispectral Index and Levels of Sedation With Propofol With/Without Remifentanil in Healthy Volunteers (SONORA)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is investigate the relationship between BIS™ and propofol with/without remifentanil across a wide range of hypnotic states.

Detailed Description
-----------------
This is a single-center, prospective, non-randomized, cross-over study to collect data to evaluate the relationship between BIS™ and anesthetic regimens. The subjects will receive two regimens of anesthesia with different drug combinations, with at least a 1-week washout period between regimens. Subjects will be sequentially assigned to start with either Propofol (P) or Propofol with 4 ng/ml of Remifentanil (R) regimens while BIS™ bilateral sensor placed on the subject's forehead. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale, refer to Appendix A, will be used to measure the level of alertness in sedated subjects with Tetanic Electrical Stimulation (TES) being used once subjects reach a MOAA/S score <2.

Official Title
-----------------
Bispectral Index and Levels of Sedation With Propofol With/Without Remifentanil in Healthy Volunteers (SONORA)

Conditions
-----------------
Anesthesia

Intervention / Treatment
-----------------
* Device: BIS


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy (ASA physical status 1), male or female subjects between the ages of 18 to 60 years; Completion of a health screening for a medical history by a licensed physician, nurse practitioner or physician assistant; Vital signs must be within the following ranges to be included: Vital signs measured sitting after 3 minutes rest; heart rate: 45-90 bpm; systolic blood pressure: 110-140; diastolic blood pressure: 50-90. Out-of-range vital signs may be repeated once. [Pre-dose vital signs will be assessed by the Principal Investigator or designee (e.g., a medically qualified sub-investigator) before study drug administration. The Principal Investigator or designee will verify the eligibility of each subject before dosing]; Exclusion Criteria: Has severe contact allergies that may cause a reaction to standard adhesive materials found in pulse oximetry sensors, ECG electrodes, respiration monitor electrodes, or other medical sensors [self-reported]; Known neurological disorder (e.g., epilepsy, the presence of a brain tumor, a history of brain surgery, hydrocephalic disorders, depression needing treatment with anti-depressive drugs, a history of brain trauma) [self-reported and assessment by PI or delegate]; Known cardiovascular disease (e.g., hypertension, coronary artery disease, prior acute myocardial infarction, any valvular and/or myocardial disease involving a decrease in ejection fraction, arrhythmias, which are either symptomatic or require continuous medication/ pacemaker/ automatic internal cardioverter defibrillator), current implanted pacemaker or automatic internal cardioverter defibrillator [self-reported and assessment by PI or delegate]; Has a clinically significant abnormal finding on medical history, physical examination, clinical laboratory tests, or ECG at the screening [self-reported and assessment by PI or delegate]; Recent use of psychoactive medication (e.g., benzodiazepines, antiepileptic drugs, ADHD medication, Parkinson's medication, anti-depressant drugs, opioids) [self-reported and assessment by PI or delegate]; Subjects with known gastric diseases [self-reported and assessment by PI or delegate]; Has a positive urine cotinine test or urine drug screen or oral ethanol test [POC testing]; Known history of allergic or adverse response to drugs to be administered [self-reported]; Known history of complications relating to previous general anesthesia or conscious sedation [self-reported and assessment by PI or delegate]; Known history of malignant hyperthermia [self-reported and assessment by PI or delegate]; Has a room air saturation less than 95% by pulse oximetry [measurement by PI or delegate]; Has a clinically significant abnormal ECG [assessment by PI or delegate]; Has a clinically significant abnormal pulmonary function test via spirometry [assessment by PI or delegate]; Pregnant or lactating women [assessed by urine test and self-reported]; Subjects with tattooed skin specific to the sensor placement areas (forehead, fingers, chest) [self-reported and assessment by PI or delegate]; The subject must not take any prescription medication, except female hormonal contraceptives or hormone replacement therapy, from 146 days before the dosing until the end-of-study visit without evaluation and approval by the Investigator. Subjects who participated in a previous clinical trial who received a required FDA approved concomitant medication, for example, naltrexone, but were not randomized may be considered for participation in this study if they meet the washout requirement [assessment by PI or delegate];

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The subjects will receive two regimens of anesthesia with different drug combinations, with at least a 1-week washout period between regimens. Subjects will be sequentially assigned to start with either propofol or propofol with remifentanil regiments.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Propofol<br>Subjects will be sequentially assigned to start with propofol or propofol with remifentanil. Propofol will be started at a concentration of 0.5 µg/ml followed by incremental increases in the target effect-site concentrations of 1.5, 2, 2.5, 3, 4, 6, and 8 µg/ml until a MOAA/S score less than 2 is reached. | Device: BIS<br>* Subjects will be sequentially assigned to the propofol or propofol and remifentanil group. The purpose is to capture the BIS value in association with these anesthetics.<br>|
| Other: Propofol with Remifentanil<br>Subjects will be sequentially assigned to start with propofol or propofol with remifentanil. Approximately 2 minutes before starting propofol, to attain an effect-site targeted concentration of remifentanil of 4 ng/ml, remifentanil will be given by a continuous infusion. Within approximately 7 minutes, the infusion rate of Remifentanil may be adjusted to maintain the effect-site concentration of remifentanil of 4 ng/ml throughout the study. | Device: BIS<br>* Subjects will be sequentially assigned to the propofol or propofol and remifentanil group. The purpose is to capture the BIS value in association with these anesthetics.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BIS50 | To determine BIS50 (BIS™ value at which 50% of patients will be unresponsive at given drug concentrations) and other dose-response parameters. BIS™ is a scale 0-100 with values near 100 represent an awake clinical state while 0 denotes the maximal EEG effect possible (i.e., an isoelectric EEG). Responsiveness is measured using the Modified Observer's Assessment of Alertness/ Sedation (MOAA/S). Below a MOAA/S of 2, responsiveness is measured with Tetanic Electrical Stimulation (TES). The subject will receive one stimulation of 50mA, 50 Hz for 5 seconds. Their response, such as withdrawal of the extremity, a facial grimace, or a verbal groan will be recorded. Approximately 2 minutes after this assessment, the BIS™ value will be recorded. When the subject does not respond to the TES stimulation, they will be considered unresponsive and that BIS™ value will be used to determine the BIS50. | 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BIS95 | To determine BIS95 (BIS™ value at which 95% of patients will be unresponsive at given drug concentrations) and other dose-response parameters. BIS™ is a scale 0-100 with values near 100 represent an awake clinical state while 0 denotes the maximal EEG effect possible (i.e., an isoelectric EEG). Responsiveness is measured using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S). Below a MOAA/S of 2, responsiveness is measured with Tetanic Electrical Stimulation (TES). The subject will receive one stimulation of 50mA, 50 Hz for 5 seconds. Their response, such as withdrawal of the extremity, a facial grimace, or a verbal groan will be recorded. Approximately 2 minutes after this assessment, the BIS™ value will be recorded. When the subject does not respond to the TES stimulation, they will be considered unresponsive and that BIS™ value will be used to determine the BIS95. | 4 hours |