Trial Outcomes & Findings for Bispectral Index and Levels of Sedation With Propofol With/Without Remifentanil in Healthy Volunteers (SONORA) (NCT NCT04466384)

Last Updated: 2022-07-19

Results Overview

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.

Recruitment status

COMPLETED

Study phase

Target enrollment

34 participants

Primary outcome timeframe

4 hours

Results posted on

2022-07-19

Participant Flow

This study recruited healthy, non-smoking (or has refrained from smoking for 2 days) subjects, 18 to 60 years of age. The subjects were distributed across both sexes as equally as practical.

During the study, 34 subjects were consented. 6 subjects were inclusion / exclusion criteria screen failures after consent leaving 28 enrolled subjects. Of these 28 enrolled subjects, 4 subjects were withdrawn due to safety events leaving 24 subjects to be assigned to randomization arms.

Participant milestones

Participant milestones
Measure	Propofol First Participants first received two regimens of Propofol (first phase). After a 1-week washout period, then received two regimens of Propofol with 4 ng/ml Remifentanil (cross over phase).	First Propofol With Remifentanil Participants first received two regimens of Propofol with 4 ng/ml Remifentanil (first phase). After a 1-week washout period, then received two regimens of Propofol (cross over phase).
First Phase STARTED	14	10
First Phase COMPLETED	12	10
First Phase NOT COMPLETED	2	0
Cross Over Phase STARTED	14	10
Cross Over Phase COMPLETED	13	9
Cross Over Phase NOT COMPLETED	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Propofol First Participants first received two regimens of Propofol (first phase). After a 1-week washout period, then received two regimens of Propofol with 4 ng/ml Remifentanil (cross over phase).	First Propofol With Remifentanil Participants first received two regimens of Propofol with 4 ng/ml Remifentanil (first phase). After a 1-week washout period, then received two regimens of Propofol (cross over phase).
First Phase Protocol Violation	1	0
First Phase Missing data	1	0
Cross Over Phase Physician Decision	1	0
Cross Over Phase Withdrawal by Subject	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Randomized Study Participants n=24 Participants Baseline measures are reported for subjects who were enrolled and randomized to Propofol first or First Propofol with Remifentanil arms (n=24). Baseline measurements are not reported for subjects who were screen failures (n=6) or withdrawn due to safety events (n=4).
Age, Continuous	28.5 years STANDARD_DEVIATION 7.8 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants
Sex: Female, Male Male	15 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	23 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	10 Participants n=5 Participants
Race (NIH/OMB) White	9 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants
Region of Enrollment United States	24 participants n=5 Participants
Skin Pigmentation Very Light	7 participants n=5 Participants
Skin Pigmentation Olive Hue	4 participants n=5 Participants
Skin Pigmentation Dark Olive	3 participants n=5 Participants
Skin Pigmentation Extremely Dark	10 participants n=5 Participants

PRIMARY outcome

Timeframe: 4 hours

Population: Intention to Treat (ITT)

Outcome measures

Outcome measures
Measure	Propofol n=24 Participants 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. BIS: 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.	Propofol With Remifentanil n=24 Participants 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. BIS: 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.
BIS50	60.4 BIS50 Index Score Interval 57.7 to 63.0	71.6 BIS50 Index Score Interval 69.0 to 74.6

SECONDARY outcome

Timeframe: 4 hours

Population: Intention to Treat (ITT)

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.

Outcome measures

Outcome measures
Measure	Propofol n=24 Participants 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. BIS: 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.	Propofol With Remifentanil n=24 Participants 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. BIS: 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.
BIS95	47.7 BIS95 index score Interval 40.5 to 51.7	63.1 BIS95 index score Interval 57.3 to 66.2

Adverse Events

Propofol First (First Phase)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

First Propofol With Remifentanil (First Phase)

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Propofol First (Cross Over Phase)

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

First Propofol With Remifentanil (Cross Over Phase)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Propofol First (First Phase) n=14 participants at risk Participants first received two regimens of Propofol (first phase). After a 1-week washout period, then received two regimens of Propofol with 4 ng/ml Remifentanil (cross over phase).	First Propofol With Remifentanil (First Phase) n=10 participants at risk Participants first received two regimens of Propofol with 4 ng/ml Remifentanil (first phase). After a 1-week washout period, then received two regimens of Propofol (cross over phase).	Propofol First (Cross Over Phase) n=14 participants at risk Participants first received two regimens of Propofol (first phase). After a 1-week washout period, then received two regimens of Propofol with 4 ng/ml Remifentanil (cross over phase).	First Propofol With Remifentanil (Cross Over Phase) n=10 participants at risk Participants first received two regimens of Propofol with 4 ng/ml Remifentanil (first phase). After a 1-week washout period, then received two regimens of Propofol (cross over phase).
Gastrointestinal disorders Haematemesis	0.00% 0/14 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	0.00% 0/10 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	7.1% 1/14 • Number of events 1 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	0.00% 0/10 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).
Gastrointestinal disorders Nausea	0.00% 0/14 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	20.0% 2/10 • Number of events 2 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	7.1% 1/14 • Number of events 1 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	0.00% 0/10 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).
Nervous system disorders Headache	0.00% 0/14 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	0.00% 0/10 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	28.6% 4/14 • Number of events 4 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	0.00% 0/10 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).
Infections and infestations COVID-19	0.00% 0/14 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	10.0% 1/10 • Number of events 1 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	0.00% 0/14 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	0.00% 0/10 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/14 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	0.00% 0/10 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	7.1% 1/14 • Number of events 1 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	0.00% 0/10 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/14 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	0.00% 0/10 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	7.1% 1/14 • Number of events 1 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).	0.00% 0/10 • 48 hours For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).

Additional Information

Ami Stuart PhD

Medtronic

Phone: 8017934800

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place