Surgery
Conditions
Brief summary
Determine the optimal dose of IV N-acetylcysteine (NAC) to produce opioid reduction following spine surgery and estimate the difference in opioid consumption between placebo and the selected optimal dose.
Detailed description
First 20 subjects: 5 participants will be randomized to each dose group (placebo, 50, 100, and 150 mg/kg) to estimate the dose response curve and to identify the optimal dose. If the dose response curve is adequate and the optimal dose identified, 15 additional participants will be randomized to placebo and 15 to the optimal dose to estimate the difference in opioid consumption between participants on placebo vs. the optimal dose. (Total of 50 subjects with 20 from dose response curve and 30 to estimate the difference in opioid consumption.) If the dose response curve is not adequate after the initial 20 subjects 5 per each dose group, then an additional 5 participants will be randomized and to each dose group (placebo, 50, 100, and 150 mg/kg) to estimate the dose response curve and to identify the optimal dose. Once the optimal dose is identified with these initial 40 patients, 10 additional participants will be randomized to placebo and 10 to the optimal dose to estimate the difference in opioid consumption between participants on placebo vs. the optimal dose. (60 patients total with 40 to create the dose response curve and 20 more to estimate the difference in opioid consumption.) A sample size of 20 subjects per group (placebo and optimal dose) allows us to estimate a 95% confidence interval for the mean difference in opioid consumption with a width of + 0.64 standard deviations from the mean. 70 subjects may be enrolled to account for withdrawal but the study will be completed once 50 or 60 subjects (based on the number of subjects required to create the dose response curve) have completed the protocol.
Interventions
DRUGDose Response Curve Placebo
5 participants will be randomized to the placebo group to estimate the dose response curve and to identify the optimal dose.
DRUGDose Response Curve N-acetylcysteine 50 mg/kg
5 participants will be randomized to the N-acetylcysteine 50 mg/kg group to estimate the dose response curve and to identify the optimal dose.
DRUGDose Response Curve N-acetylcysteine 100 mg/kg
5 participants will be randomized to the N-acetylcysteine 100 mg/kg group to estimate the dose response curve and to identify the optimal dose.
DRUGDose Response Curve N-acetylcysteine 150 mg/kg
5 participants will be randomized to the N-acetylcysteine 150 mg/kg group to estimate the dose response curve and to identify the optimal dose.
DRUGOpioid Reduction with Optimal N-acetylcysteine Dose
Once the optimal N-acetylcysteinedose is identified, 15 participants will be randomized to the optimal dose (50,100, or 150 mg/kg) to estimate the difference in opioid consumption between patients administered optimal N-acetylcysteine dose or placebo.
DRUGPlacebo
15 Participants will be randomized to placebo to estimate the difference in opioid consumption between patients administered optimal N-acetylcysteine dose or placebo.
Sponsors
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
PHASE I. First 20 subjects (4 arms): We will initially randomize 5 patients to each dose group (placebo, 50, 100, and 150 mg/kg) to estimate the dose response curve and to identify the optimal dose. After enrollment of the first 20 patients, the study will undergo review by the study team and statistician. PHASE II: (2 arms) If the dose response curve is adequate and the optimal dose identified, 15 additional participants will be randomized to placebo and 15 to the optimal dose to estimate the difference in opioid consumption between patients on placebo vs. the optimal dose. Primary and secondary outcomes will be evaluated only for the placebo and optimal NAC groups.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Undergoing elective spine surgery involving 4 levels or less of the thoracic, lumbar, or sacral spine. * 18 years of age and older.
Exclusion criteria
* Less than 40kg in weight. * Unable to provide written, informed consent. * History of an adverse or anaphylactoid reaction to acetylcysteine. * Active asthma, wheezing, or using inhaled bronchodilators. * Pregnant Women * Known blood clotting deficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Opioid Consumption 12 Hours Post Operative | 12 hours | Post operative opioid consumption in the 12 hours that occur post-operatively. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Opioid Consumption Every 6 Hours Post Operative | 6-48 hours | Post operative opioid consumption ry 6 hours post operative. Data are reported as mean (95% CI) or mean difference (95% CI) estimated from a linear mixed model of opioid consumption over time including main effects for treatment group, postoperative time, and the interaction between treatment group and postoperative time and a random subject effect. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NAC (0mg/kg) (n=20) 5 participants randomized to the placebo group to estimate the dose response curve and to identify the optimal dose. Then 15 more patients enrolled for final comparison versus optimal dose. | 20 |
| NAC (50mg/kg) (n=5) 5 participants will be randomized to the N-acetylcysteine 50 mg/kg group to estimate the dose response curve and to identify the optimal dose. | 5 |
| NAC (100mg/kg) (n=5) 5 participants will be randomized to the N-acetylcysteine 100 mg/kg group to estimate the dose response curve and to identify the optimal dose. | 5 |
| NAC (150mg/kg) (n=20) 5 participants will be randomized to the N-acetylcysteine 150 mg/kg group to estimate the dose response curve and to identify the optimal dose. Since optimal not identified with dose response curve, 15 more subjects enrolled in 150 mg/kg group for final comparison with placebo. | 20 |
| Total | 50 |
Baseline characteristics
| Characteristic | NAC (0mg/kg) | NAC (50mg/kg) | NAC (100mg/kg) | NAC (150mg/kg) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 12.8 | 68.4 years STANDARD_DEVIATION 8.21 | 71.6 years STANDARD_DEVIATION 7.54 | 67.4 years STANDARD_DEVIATION 6.62 | 64.4 years STANDARD_DEVIATION 10.2 |
| Home opioid use (yes) | 5 participants | 2 participants | 1 participants | 5 participants | 13 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 0 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 3 Participants | 5 Participants | 16 Participants | 39 Participants |
| Region of Enrollment United States | 20 participants | 5 participants | 5 participants | 20 participants | 50 participants |
| Sex: Female, Male Female | 9 Participants | 2 Participants | 2 Participants | 7 Participants | 20 Participants |
| Sex: Female, Male Male | 11 Participants | 3 Participants | 3 Participants | 13 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 5 | 0 / 5 | 0 / 20 |
| other Total, other adverse events | 0 / 20 | 0 / 5 | 0 / 5 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 5 | 0 / 5 | 0 / 20 |
Outcome results
Primary
Opioid Consumption 12 Hours Post Operative
Post operative opioid consumption in the 12 hours that occur post-operatively.
Time frame: 12 hours
Population: Primary and secondary outcomes were only be evaluated for the placebo and optimal NAC groups. Data are reported as mean (95% CI) estimated from a linear mixed model of opioid consumption over time including main effects for treatment group, postoperative time, and the interaction between treatment group and postoperative time and a random subject effect.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Opioid Consumption 12 Hours Post Operative | 19.4 IV morphine mg equivalents |
| N-acetylcysteine (NAC) | Opioid Consumption 12 Hours Post Operative | 15.6 IV morphine mg equivalents |
Secondary
Opioid Consumption Every 6 Hours Post Operative
Post operative opioid consumption ry 6 hours post operative. Data are reported as mean (95% CI) or mean difference (95% CI) estimated from a linear mixed model of opioid consumption over time including main effects for treatment group, postoperative time, and the interaction between treatment group and postoperative time and a random subject effect.
Time frame: 6-48 hours
Population: Primary and secondary outcomes were only be evaluated for the placebo and optimal NAC groups. Data are reported as mean (95% CI) estimated from a linear mixed model of opioid consumption over time including main effects for treatment group, postoperative time, and the interaction between treatment group and postoperative time and a random subject effect.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Opioid Consumption Every 6 Hours Post Operative | 24 hours | 29.6 IV morphine mg equivalents |
| Placebo | Opioid Consumption Every 6 Hours Post Operative | 36 hours | 37.9 IV morphine mg equivalents |
| Placebo | Opioid Consumption Every 6 Hours Post Operative | 18 hours | 25.0 IV morphine mg equivalents |
| Placebo | Opioid Consumption Every 6 Hours Post Operative | 42 | 40.9 IV morphine mg equivalents |
| Placebo | Opioid Consumption Every 6 Hours Post Operative | 30 hours | 34.0 IV morphine mg equivalents |
| Placebo | Opioid Consumption Every 6 Hours Post Operative | 48 | 43.3 IV morphine mg equivalents |
| Placebo | Opioid Consumption Every 6 Hours Post Operative | 6 hours | 14.6 IV morphine mg equivalents |
| N-acetylcysteine (NAC) | Opioid Consumption Every 6 Hours Post Operative | 48 | 34.9 IV morphine mg equivalents |
| N-acetylcysteine (NAC) | Opioid Consumption Every 6 Hours Post Operative | 6 hours | 12.0 IV morphine mg equivalents |
| N-acetylcysteine (NAC) | Opioid Consumption Every 6 Hours Post Operative | 18 hours | 19.9 IV morphine mg equivalents |
| N-acetylcysteine (NAC) | Opioid Consumption Every 6 Hours Post Operative | 24 hours | 24.7 IV morphine mg equivalents |
| N-acetylcysteine (NAC) | Opioid Consumption Every 6 Hours Post Operative | 30 hours | 27.2 IV morphine mg equivalents |
| N-acetylcysteine (NAC) | Opioid Consumption Every 6 Hours Post Operative | 36 hours | 29.7 IV morphine mg equivalents |
| N-acetylcysteine (NAC) | Opioid Consumption Every 6 Hours Post Operative | 42 | 33.1 IV morphine mg equivalents |