Arthroscopy, Bunionectomy, Carpal Tunnel, Osteotomy
Conditions
Keywords
AQUAVAN® Injection, Midazolam, Minor surgical procedures, Sedation
Brief summary
The purpose of this study is to determine the safety, tolerability, and efficacy of AQUAVAN® Injection when used for mild-to-moderate sedation in patients undergoing minor surgical procedures.
Detailed description
Randomized, open label, multi-center,midazolam adaptive dose ranging study, in which several dose levels of AQUAVAN® Injection and fentanyl citrate injection will be investigated to produce a desired sedation level in patients undergoing minor surgical and/or therapeutic procedures. A desired sedative dose/dose range and dosing paradigm will be identified based on pre-set criteria using the Modified Observer's Assessment of Alertness/Sedation (OAA/S). The desired sedative dose/dose range and dosing paradigm of AQUAVAN® Injection is defined as one that consistently provides mild to moderate sedation (Modified OAA/S between 2 and 4 inclusive) in majority of patients who are pre-medicated with fentanyl citrate injection. Midazolam is the most widely used i.v. agent for minimal-to-moderate sedation. The dose range of midazolam to induce minimal to moderate sedation was based on standard clinical practice. \[new paragraph\] All patients were pre-medicated with fentanyl citrate as an analgesic. The outpatient setting has become increasingly popular for various types of medical procedures requiring sedation. In outpatient minor surgical procedures, sedation agents are used to provide mild-to-moderate sedation and are used with other medicines for pain management. Surgeons have searched for alternative treatments to use in the outpatient setting that would provide a faster recovery time with minimal post-procedure amnesia. This injection is used following pretreatment with fentanyl citrate for pain management.
Interventions
Sponsors
PPD Development, LP
Covance
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient provided signed/dated Informed Consent and HIPAA Authorization after receiving a full explanation of the extent and nature of the study. 2. Patient was at least 18 years of age at the time of screening. (Prior to Amendment 1, dated 03 February 2005, this criterion restricted enrollment to patients who were ≥18 and ≤65 years of age. To ensure that safe dosing levels were administered to patients \>65 years of age, AQUAVAN and midazolam dosing levels were reduced when compared with patients between 18 and 65 years of age, inclusive. The majority of patients were enrolled prior to 03 February 2005.) 3. Female patient must have been surgically sterile, postmenopausal, or not pregnant or lactating, and must have been using an acceptable method of birth control for at least 1 month prior to dosing, with a negative urine pregnancy test result at screening and predosing periods. 4. Patient met the American Society of Anesthesiologists (ASA) Physical Status Classification System of I to III. 5. Patient may have been an inpatient or outpatient scheduled to undergo a single minor surgical and/or therapeutic procedure.
Exclusion criteria
1. Patient had a history of allergic reaction or hypersensitivity to any anesthetic agent, narcotic, or benzodiazepine. 2. Patient did not meet nils per os (NPO) status per ASA Guideline or institution's guideline. 3. Patient had condition(s) that, in the opinion of the Investigator, could interfere with appropriate airway management. 4. Patient had participated in an investigational drug study within 1 month prior to study start. 5. Patient had a history of mental or visual impairment that would not permit successful measurement of cognitive evaluations. 6. Patient was unwilling to adhere to pre- and postprocedural instructions. 7. The use of fentanyl or midazolam was contraindicated for the patient. 8. Patient had experienced multiple concurrent injuries or trauma. 9. Patient was scheduled to undergo multiple same-day procedures (eg, bunionectomies on both feet).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Successful Sedation of Subjects, Defined for a Subject as Having 3 Consecutive Scores ≤ 4 on the Modified Observer's Assessment of Alertness/Sedation Scale and Completing the Procedure w/o Alternative Sedative Medications/w/o Manual/Mechanical Ventilation | Sedation success was assessed at 2 minute intervals until the end of the procedure | The Modified OAA/S (MOAA/S) scale is based on a validated, 6-point rating scale. Scores are not combined. Score 5 (alert) -- responds readily to name spoken in normal tone Score 4 -- Lethargic response to name spoken in normal tone Score 3 -- Responds only after name is called loudly and/or repeatedly Score 2 -- Responds only after mild prodding or shaking Score 1 -- Responds only after painful trapezius squeeze Score 0 -- Does not respond to painful trapezius squeeze |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Fully Alert From the End of the Procedure | At 2-minute intervals from the end of the procedure until the subject met the criteria for Fully Alert status | Time to Fully Alert, defined as the time to the first of 3 consecutive Modified OAA/S scores of 5 from the end of the surgical procedure, was summarized. |
Participant flow
Recruitment details
This study recruited at 18 centers in the US during the period of 29-Oct-2004 to 24 Mar 2005.
Pre-assignment details
After enrollment and before randomization all subjects, irrespective of treatment group assignment,received fentanyl citrate injection 0.5 µg/kg to 1 µg/kg(based on age)as an analgesic pretreatment 5 minutes prior to the administration of either fospropofol disodium (Also known as,LUSEDRA and formerly known as AQUAVAN) or midazolam midazolam HCl).
Participants by arm
| Arm | Count |
|---|---|
| Fospropofol Disodium 525 mg to 980 mg (dose based on weight and age): one initial intravenous (i.v.) bolus dose. Supplemental doses of fospropofol disodium 105 mg to 140 mg (based on weight and age) were administered as needed. | 121 |
| Midazolam 0.5 to 2 mg (dose based on weight and age): one initial i.v. bolus dose. Supplemental doses of midazolam 0.25 mg to 1 mg (based on weight and age) were administered as needed. | 42 |
| Total | 163 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 1 | 0 |
Baseline characteristics
| Characteristic | Midazolam | Fospropofol Disodium | Total |
|---|---|---|---|
| Age, Continuous | 45.3 years STANDARD_DEVIATION 11.5 | 45.3 years STANDARD_DEVIATION 11 | 45.3 years STANDARD_DEVIATION 11.1 |
| American Society of Anesthesiologists Status (ASA) I (A normal healthy patient) | 19 particpants | 48 particpants | 67 particpants |
| American Society of Anesthesiologists Status (ASA) II (A patient with mild systemic disease) | 21 particpants | 71 particpants | 92 particpants |
| American Society of Anesthesiologists Status (ASA) III (A patient with severe systemic disease) | 2 particpants | 2 particpants | 4 particpants |
| History of Adverse Reactions following a Previous Sedation No | 37 participants | 111 participants | 148 participants |
| History of Adverse Reactions following a Previous Sedation No history of sedation | 3 participants | 7 participants | 10 participants |
| History of Adverse Reactions following a Previous Sedation Yes | 2 participants | 3 participants | 5 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 10 participants | 19 participants | 29 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 participants | 14 participants | 17 participants |
| Race/Ethnicity, Customized More than one race | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 28 participants | 87 participants | 115 participants |
| Sex: Female, Male Female | 24 Participants | 84 Participants | 108 Participants |
| Sex: Female, Male Male | 18 Participants | 37 Participants | 55 Participants |
| Weight (kg) <55 | 0 particpants | 7 particpants | 7 particpants |
| Weight (kg) 55 to > 80 | 14 particpants | 41 particpants | 55 particpants |
| Weight (kg) >80 | 28 particpants | 73 particpants | 101 particpants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 104 / 121 | 31 / 42 |
| serious Total, serious adverse events | 1 / 121 | 0 / 42 |
Outcome results
Primary
Successful Sedation of Subjects, Defined for a Subject as Having 3 Consecutive Scores ≤ 4 on the Modified Observer's Assessment of Alertness/Sedation Scale and Completing the Procedure w/o Alternative Sedative Medications/w/o Manual/Mechanical Ventilation
The Modified OAA/S (MOAA/S) scale is based on a validated, 6-point rating scale. Scores are not combined. Score 5 (alert) -- responds readily to name spoken in normal tone Score 4 -- Lethargic response to name spoken in normal tone Score 3 -- Responds only after name is called loudly and/or repeatedly Score 2 -- Responds only after mild prodding or shaking Score 1 -- Responds only after painful trapezius squeeze Score 0 -- Does not respond to painful trapezius squeeze
Time frame: Sedation success was assessed at 2 minute intervals until the end of the procedure
Population: The pP1 and mITT population included all subjects randomized,received either fospropofol disodium or midazolam, had at least 1 postdose clinical assessment, and were not terminated due to the Investigator's decision for nonstudy drug related findings. A 95% confidence interval for the sedation success rate was calculated for each treatment group.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Fospropofol Disodium | Successful Sedation of Subjects, Defined for a Subject as Having 3 Consecutive Scores ≤ 4 on the Modified Observer's Assessment of Alertness/Sedation Scale and Completing the Procedure w/o Alternative Sedative Medications/w/o Manual/Mechanical Ventilation | pPI Population Sedation Success | 94.2 participants | 95% Confidence Interval 94.2 |
| Fospropofol Disodium | Successful Sedation of Subjects, Defined for a Subject as Having 3 Consecutive Scores ≤ 4 on the Modified Observer's Assessment of Alertness/Sedation Scale and Completing the Procedure w/o Alternative Sedative Medications/w/o Manual/Mechanical Ventilation | mITT Population Sedation Success | 94.2 participants | — |
| Midazolam | Successful Sedation of Subjects, Defined for a Subject as Having 3 Consecutive Scores ≤ 4 on the Modified Observer's Assessment of Alertness/Sedation Scale and Completing the Procedure w/o Alternative Sedative Medications/w/o Manual/Mechanical Ventilation | pPI Population Sedation Success | 78.6 participants | — |
| Midazolam | Successful Sedation of Subjects, Defined for a Subject as Having 3 Consecutive Scores ≤ 4 on the Modified Observer's Assessment of Alertness/Sedation Scale and Completing the Procedure w/o Alternative Sedative Medications/w/o Manual/Mechanical Ventilation | mITT Population Sedation Success | 78.6 participants | — |
Secondary
Time to Fully Alert From the End of the Procedure
Time to Fully Alert, defined as the time to the first of 3 consecutive Modified OAA/S scores of 5 from the end of the surgical procedure, was summarized.
Time frame: At 2-minute intervals from the end of the procedure until the subject met the criteria for Fully Alert status
Population: The primary analysis for the secondary efficacy endpoint was based on the mITT population. Missing values or incomplete data were not imputed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fospropofol Disodium | Time to Fully Alert From the End of the Procedure | 8.4 minutes | Standard Deviation 10.9 |
| Midazolam | Time to Fully Alert From the End of the Procedure | 4.1 minutes | Standard Deviation 5.4 |