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

• Sponsor: Medtronic - MITG (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04466384
• Collaborator: (none)
• Enrollment: 34
• Location: 1
• Arms: 2
• Actual Duration (Months): 6.7
• Patients Per Site Per Month: 5.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Anesthesia	Device: BIS	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Intervention 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.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)
• Primary Purpose: Other
• Official Title: Bispectral Index and Levels of Sedation With Propofol With/Without Remifentanil in Healthy Volunteers (SONORA)
• Actual Study Start Date: Aug 11, 2020
• Actual Primary Completion Date: Mar 3, 2021
• Actual Study Completion Date: Mar 3, 2021

Arms and Interventions

Arm	Intervention/Treatment
Other: Propofol 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; 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.
Other: Propofol with Remifentanil 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; 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.

Outcome Measures

Primary Outcome Measures

1. BIS50 [4 hours]

   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.

Secondary Outcome Measures

1. BIS95 [4 hours]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Healthy (ASA physical status 1), male or female subjects between the ages of 18 to 60 years;

2. Completion of a health screening for a medical history by a licensed physician, nurse practitioner or physician assistant;

3. 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:

1. 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];

2. 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];

3. 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];

4. 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];

5. 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];

6. Subjects with known gastric diseases [self-reported and assessment by PI or delegate];

7. Has a positive urine cotinine test or urine drug screen or oral ethanol test [POC testing];

8. Known history of allergic or adverse response to drugs to be administered [self-reported];

9. Known history of complications relating to previous general anesthesia or conscious sedation [self-reported and assessment by PI or delegate];

10. Known history of malignant hyperthermia [self-reported and assessment by PI or delegate];

11. Has a room air saturation less than 95% by pulse oximetry [measurement by PI or delegate];

12. Has a clinically significant abnormal ECG [assessment by PI or delegate];

13. Has a clinically significant abnormal pulmonary function test via spirometry [assessment by PI or delegate];

14. Pregnant or lactating women [assessed by urine test and self-reported];

15. Subjects with tattooed skin specific to the sensor placement areas (forehead, fingers, chest) [self-reported and assessment by PI or delegate];

16. 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];

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Medtronic - MITG

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Sep 28, 2020
• Statistical Analysis Plan - Mar 5, 2020

More Information

Publications

None provided.

• Responsible Party: Medtronic - MITG
• ClinicalTrials.gov Identifier: NCT04466384
• Other Study ID Numbers: MDT19049SONORA
• First Posted: Jul 10, 2020
• Last Update Posted: Jul 19, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	Propofol First	First Propofol With Remifentanil
Arm/Group Description	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).	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).
Period Title: First Phase
STARTED	14	10
COMPLETED	12	10
NOT COMPLETED	2	0
Period Title: First Phase
STARTED	14	10
COMPLETED	13	9
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Randomized Study Participants
Arm/Group Description	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).
Overall Participants	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.5 (7.8)
Sex: Female, Male (Count of Participants)
Female	9 37.5%
Male	15 62.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.2%
Not Hispanic or Latino	23 95.8%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	4 16.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	10 41.7%
White	9 37.5%
More than one race	0 0%
Unknown or Not Reported	1 4.2%
Region of Enrollment (participants) [Number]
United States	24 100%
Skin Pigmentation (participants) [Number]
Very Light	7 29.2%
Olive Hue	4 16.7%
Dark Olive	3 12.5%
Extremely Dark	10 41.7%

Outcome Measures

1. Primary Outcome

Title	BIS50
Description	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.
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT)

Arm/Group Title	Propofol	Propofol With Remifentanil
Arm/Group Description	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.	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.
Measure Participants	24	24
Number (95% Confidence Interval) [BIS50 Index Score]	60.4	71.6

2. Secondary Outcome

Title	BIS95
Description	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.
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT)

Arm/Group Title	Propofol	Propofol With Remifentanil
Arm/Group Description	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.	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.
Measure Participants	24	24
Number (95% Confidence Interval) [BIS95 index score]	47.7	63.1

Adverse Events

Time Frame	48 hours
Adverse Event Reporting Description	For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).
Arm/Group Title	Propofol First (First Phase)		First Propofol With Remifentanil (First Phase)		Propofol First (Cross Over Phase)		First Propofol With Remifentanil (Cross Over Phase)
Arm/Group Description	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).		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).		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).		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).
All Cause Mortality
	Propofol First (First Phase)		First Propofol With Remifentanil (First Phase)		Propofol First (Cross Over Phase)		First Propofol With Remifentanil (Cross Over Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/10 (0%)		0/14 (0%)		0/10 (0%)
Serious Adverse Events
	Propofol First (First Phase)		First Propofol With Remifentanil (First Phase)		Propofol First (Cross Over Phase)		First Propofol With Remifentanil (Cross Over Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/10 (0%)		0/14 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Propofol First (First Phase)		First Propofol With Remifentanil (First Phase)		Propofol First (Cross Over Phase)		First Propofol With Remifentanil (Cross Over Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		3/10 (30%)		8/14 (57.1%)		0/10 (0%)
Gastrointestinal disorders
Haematemesis	0/14 (0%)	0	0/10 (0%)	0	1/14 (7.1%)	1	0/10 (0%)	0
Nausea	0/14 (0%)	0	2/10 (20%)	2	1/14 (7.1%)	1	0/10 (0%)	0
Infections and infestations
COVID-19	0/14 (0%)	0	1/10 (10%)	1	0/14 (0%)	0	0/10 (0%)	0
Musculoskeletal and connective tissue disorders
Myalgia	0/14 (0%)	0	0/10 (0%)	0	1/14 (7.1%)	1	0/10 (0%)	0
Nervous system disorders
Headache	0/14 (0%)	0	0/10 (0%)	0	4/14 (28.6%)	4	0/10 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/14 (0%)	0	0/10 (0%)	0	1/14 (7.1%)	1	0/10 (0%)	0

Limitations/Caveats

While there are known risks with providing general anesthesia to adults, this study was deemed to be a non-significant risk study.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.