Post Operative Pain
Conditions
Keywords
Post-operative pain, non-opioid analgesic, opioid reduction, laparoscopic cholecystectomy, laparoscopic surgery, bupivacaine, extended release, locally acting analgesic
Brief summary
This is a research study of SABER® -Bupivacaine, an experimental medication designed to reduce pain for up to 3 days after surgery. Given once by the surgeon at the end of surgery, SABER® - Bupivacaine delivers a locally-acting pain reliever directly to the surgical wound. The purpose of this study is to measure how well it works in reducing pain after laparoscopic cholecystectomy (surgery to remove the gall bladder) and to investigate the safety of SABER®-Bupivacaine (its side effects).
Interventions
DRUGSABER-Bupivacaine (Part 1)
5 ml once at end of surgery
DRUGSABER-Bupivacaine (Part 2)
5 ml once at end of surgery
DRUGSaline Placebo
5 ml once at end of surgery
DRUGBupivacaine HCl
0.5%, 15 ml, once at end of surgery
Sponsors
Durect
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients scheduled for elective outpatient laparoscopic cholecystectomy using a conventional 4-port laparoscopic procedure. * Must be able and willing to provide written informed consent, complete trial-related procedures, and communicate with the trial staff. * Males and females 18 years of age or older. * ASA Class I, II, or III. * Patients of child-bearing potential must agree to use a medically acceptable method of contraception to prevent pregnancy for the duration of their participation in the trial. * Must be living close enough to the investigative site to attend the four scheduled follow-up clinic visits.
Exclusion criteria
* Pregnant or nursing females. * Patients with absolute or relative contraindications to laparoscopic cholecystectomy. * Patients with prior midline abdominal surgery who are at risk for adhesions that may complicate laparoscopic cholecystectomy and/or accurate pain assessments. * Patients requiring emergency surgery or urgent surgery (fewer than 5 days between screening and surgery). * Patients with a pre-planned overnight stay or pre-planned hospital admission. * Patients scheduled for single incision, mini trocars, natural orifice transluminal endoscopic surgery (NOTES), robotic laparoscopic procedures, or any procedure (other than cholangiograms and minimal adhesiolysis) in addition to laparoscopic cholecystectomy. * Patients with known hypersensitivity to amide local anesthetics such as bupivacaine. * Patients with acute pain that is not due to cholecystitis. * Patients with a history of chronic pain unrelated to gallbladder disease. * Patients with ongoing depression or psychosis. * Patients undergoing long-term treatment with opioids or other analgesics, including acetaminophen, NSAIDs, anticonvulsants (gabapentin or pregabalin), and antidepressants (SSRIs, SNRIs, and tricyclics), but not including daily low-dose aspirin. * Patients who are being treated chronically with systemic corticosteroids or who will require peri-operative corticosteroids because of adrenal insufficiency (inhalational or topical corticosteroids are permitted). * Patients who may be unsuitable for opioid administration (such as sensitivity \[e.g., history of severe nausea and vomiting\] hypersensitivity, known history of abuse or addiction, or unwillingness to take prescribed rescue opioids). * Use of anticoagulants and antiplatelet drugs (with exception of low dose aspirin) in the 1 week prior to surgery. * Patients who are incapable of operating the electronic diary. * Patients participating in any other trial with an investigational drug or device concurrently or less than 30 days prior to surgery for this trial. * Patients who, in the Investigator's opinion, should not participate in the trial or may not be capable of following the trial procedures for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Intensity on Movement From 0-48 Hours Post-Treatment | Assessed from 0 to 48 hours post-dose, summary measure (see description) reported. | A derived measure computed based on a patient-reported numerical pain rating scale assessing pain as a whole number from 0 (no pain) to 10 (worst pain imaginable) when the subject sits up from a supine position. This measure was evaluated by electronic diary at 13 planned time points from 0 to 48 hours post-treatment. The values reported are mean pain scores for each treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total IV Morphine-equivalent Dose of Rescue Opioids | 0-72 hrs. post dose (after surgery) | IV morphine-equivalent dose |
| Composite Endpoint of Silverman's Integrated Analgesic (SIA) Assessment Score | 0 to 72 hours | Score of Integrated Analgesia (SIA) is a composite endpoint that integrates pain assessment scores with opioid use over various collections of timepoints by ranking the pain score and the opioid use separately across treatments. After the scores are computed the means are calculated across time points to provide a single overall treatment effect. The composite SIA score ranges from -200 to 200 with -200 being the best case and 200 the worst case. |
| Pain Intensity Using the NPRS-11 With Movement | Assessed from 0 to 72 hours post-dose, summary measure (see description) reported. | A derived measure computed based on a patient-reported numerical pain rating scale assessing pain as a whole number from 0 (no pain) to 10 (worst pain imaginable) when the subject sits up from a supine position. This measure was evaluated by electronic diary at 17 planned time points from 0 to 72 hours post-treatment. The values reported are mean pain scores for each treatment group. |
| Time to First Opioid Rescue Medication Use After Discharge From the PACU | From PACU Discharge to 72 Hours post-treatment | Pooled SABER-Bupivacaine parts 1 + 2 vs. Bupivacaine HCl |
| Time to PACU Discharge Eligibility as Assessed by Modified Post-Anesthesia Discharge Scoring System (mPADSS) | From admission to discharge from PACU (Approximately 0 to 12 hours) | mPADSS is a tool used to determine eligibility for discharge from the PACU after ambulatory surgery. It includes an assessment of parameters such as vital signs, activity level, nausea/vomiting, pain, and surgical bleeding. For this trial, evaluation of eligibility for PACU discharge by mPADSS has been slightly modified to provide a standardized means of assessing eligibility for PACU discharge across multiple investigative sites and also ensures that nonmedical complications, such as a missing ride home, do not interfere with evaluation of test drug effects. |
| Subjects Not Taking Rescue Medication From PACU Discharge to 72 Hours | From PACU Discharge to 72 Hours post-treatment | Pooled SABER-Bupivacaine parts 1 + 2 vs. Bupivacaine HCl |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 22 sites in the US. First subject was randomized on 17 November 2015. Study completion date was on 16 Aug 2017.
Participants by arm
| Arm | Count |
|---|---|
| SABER-Bupivacaine (Part 1) 5 ml once at end of surgery | 48 |
| Saline Placebo (Part 1) 5 ml once at end of surgery | 46 |
| SABER-Bupivacaine (Part 2) 5 ml once at end of surgery | 153 |
| Bupivacaine HCL (Part 2) 0.5%, 15 ml, once at end of surgery | 152 |
| Total | 399 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Not dosed | 2 | 0 | 5 | 4 |
| Overall Study | Other | 0 | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | SABER-Bupivacaine (Part 1) | Total | Bupivacaine HCL (Part 2) | SABER-Bupivacaine (Part 2) | Saline Placebo (Part 1) |
|---|---|---|---|---|---|
| Age, Continuous | 46.0 years STANDARD_DEVIATION 14.2 | 44.8 years STANDARD_DEVIATION 13.67 | 44.7 years STANDARD_DEVIATION 13.9 | 45.5 years STANDARD_DEVIATION 13.5 | 41.8 years STANDARD_DEVIATION 12.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 15 Participants | 6 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 26 Participants | 9 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 39 Participants | 355 Participants | 135 Participants | 141 Participants | 40 Participants |
| Region of Enrollment United States | 48 participants | 399 participants | 152 participants | 153 participants | 46 participants |
| Sex: Female, Male Female | 31 Participants | 292 Participants | 117 Participants | 115 Participants | 29 Participants |
| Sex: Female, Male Male | 17 Participants | 107 Participants | 35 Participants | 38 Participants | 17 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 / 45 | 0 / 47 | 0 / 148 | 0 / 148 |
| other Total, other adverse events | 43 / 45 | 47 / 47 | 148 / 148 | 146 / 148 |
| serious Total, serious adverse events | 1 / 45 | 0 / 47 | 5 / 148 | 3 / 148 |
Outcome results
Primary
Pain Intensity on Movement From 0-48 Hours Post-Treatment
A derived measure computed based on a patient-reported numerical pain rating scale assessing pain as a whole number from 0 (no pain) to 10 (worst pain imaginable) when the subject sits up from a supine position. This measure was evaluated by electronic diary at 13 planned time points from 0 to 48 hours post-treatment. The values reported are mean pain scores for each treatment group.
Time frame: Assessed from 0 to 48 hours post-dose, summary measure (see description) reported.
Population: mITT Population, results for only the prespecified analysis population {SABER-Bupivacaine (Part 2) and Bupivacaine HCl (Part 2)} are provided, there was no prespecified primary outcome measure that included the SABER-Bupivacaine (Part 1) arm or the Saline Placebo (Part 1) arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2/SABER-Bupivacaine | Pain Intensity on Movement From 0-48 Hours Post-Treatment | 5.55 score on a scale | Standard Error 0.065 |
| Part 2/Bupivacaine HCl | Pain Intensity on Movement From 0-48 Hours Post-Treatment | 5.87 score on a scale | Standard Error 0.059 |
Comparison: Pain Intensity on Movement 0-48 hrp-value: 0.12495% CI: [-0.84, 0.1]ANOVA
Secondary
Composite Endpoint of Silverman's Integrated Analgesic (SIA) Assessment Score
Score of Integrated Analgesia (SIA) is a composite endpoint that integrates pain assessment scores with opioid use over various collections of timepoints by ranking the pain score and the opioid use separately across treatments. After the scores are computed the means are calculated across time points to provide a single overall treatment effect. The composite SIA score ranges from -200 to 200 with -200 being the best case and 200 the worst case.
Time frame: 0 to 72 hours
Population: mITT Population, results for only the prespecified analysis population {SABER-Bupivacaine (Part 1 and Part 2 combined) and Bupivacaine HCl (Part 2)} are provided, there was no prespecified secondary outcome measure that included the Saline Placebo (Part 1) arm or the SABER-Bupivacaine (Part 1) arm as a standalone treatment group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2/SABER-Bupivacaine | Composite Endpoint of Silverman's Integrated Analgesic (SIA) Assessment Score | -17.3 score on a scale | Standard Error 8.83 |
| Part 2/Bupivacaine HCl | Composite Endpoint of Silverman's Integrated Analgesic (SIA) Assessment Score | -1.5 score on a scale | Standard Error 9.33 |
Secondary
Pain Intensity Using the NPRS-11 With Movement
A derived measure computed based on a patient-reported numerical pain rating scale assessing pain as a whole number from 0 (no pain) to 10 (worst pain imaginable) when the subject sits up from a supine position. This measure was evaluated by electronic diary at 17 planned time points from 0 to 72 hours post-treatment. The values reported are mean pain scores for each treatment group.
Time frame: Assessed from 0 to 72 hours post-dose, summary measure (see description) reported.
Population: mITT Population, results for only the prespecified analysis population {SABER-Bupivacaine (Part 1 and Part 2 combined) and Bupivacaine HCl (Part 2)} are provided, there was no prespecified secondary outcome measure that included the Saline Placebo (Part 1) arm or the SABER-Bupivacaine (Part 1) arm as a standalone treatment group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2/SABER-Bupivacaine | Pain Intensity Using the NPRS-11 With Movement | 4.94 score on a scale | Standard Error 0.049 |
| Part 2/Bupivacaine HCl | Pain Intensity Using the NPRS-11 With Movement | 5.40 score on a scale | Standard Error 0.052 |
Secondary
Subjects Not Taking Rescue Medication From PACU Discharge to 72 Hours
Pooled SABER-Bupivacaine parts 1 + 2 vs. Bupivacaine HCl
Time frame: From PACU Discharge to 72 Hours post-treatment
Population: mITT Population, results for only the prespecified analysis population {SABER-Bupivacaine (Part 1 and Part 2 combined) and Bupivacaine HCl (Part 2)} are provided, there was no prespecified secondary outcome measure that included the Saline Placebo (Part 1) arm or the SABER-Bupivacaine (Part 1) arm as a standalone treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2/SABER-Bupivacaine | Subjects Not Taking Rescue Medication From PACU Discharge to 72 Hours | 57 participants |
| Part 2/Bupivacaine HCl | Subjects Not Taking Rescue Medication From PACU Discharge to 72 Hours | 42 participants |
Secondary
Time to First Opioid Rescue Medication Use After Discharge From the PACU
Pooled SABER-Bupivacaine parts 1 + 2 vs. Bupivacaine HCl
Time frame: From PACU Discharge to 72 Hours post-treatment
Population: mITT Population, results for only the prespecified analysis population {SABER-Bupivacaine (Part 1 and Part 2 combined) and Bupivacaine HCl (Part 2)} are provided, there was no prespecified secondary outcome measure that included the Saline Placebo (Part 1) arm or the SABER-Bupivacaine (Part 1) arm as a standalone treatment group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2/SABER-Bupivacaine | Time to First Opioid Rescue Medication Use After Discharge From the PACU | 5.5 hours |
| Part 2/Bupivacaine HCl | Time to First Opioid Rescue Medication Use After Discharge From the PACU | 6.1 hours |
Secondary
Time to PACU Discharge Eligibility as Assessed by Modified Post-Anesthesia Discharge Scoring System (mPADSS)
mPADSS is a tool used to determine eligibility for discharge from the PACU after ambulatory surgery. It includes an assessment of parameters such as vital signs, activity level, nausea/vomiting, pain, and surgical bleeding. For this trial, evaluation of eligibility for PACU discharge by mPADSS has been slightly modified to provide a standardized means of assessing eligibility for PACU discharge across multiple investigative sites and also ensures that nonmedical complications, such as a missing ride home, do not interfere with evaluation of test drug effects.
Time frame: From admission to discharge from PACU (Approximately 0 to 12 hours)
Population: mITT Population, results for only the prespecified analysis population {SABER-Bupivacaine (Part 1 and Part 2 combined) and Bupivacaine HCl (Part 2)} are provided, there was no prespecified secondary outcome measure that included the Saline Placebo (Part 1) arm or the SABER-Bupivacaine (Part 1) arm as a standalone treatment group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2/SABER-Bupivacaine | Time to PACU Discharge Eligibility as Assessed by Modified Post-Anesthesia Discharge Scoring System (mPADSS) | 1.8 hours |
| Part 2/Bupivacaine HCl | Time to PACU Discharge Eligibility as Assessed by Modified Post-Anesthesia Discharge Scoring System (mPADSS) | 1.9 hours |
Secondary
Total IV Morphine-equivalent Dose of Rescue Opioids
IV morphine-equivalent dose
Time frame: 0-72 hrs. post dose (after surgery)
Population: mITT Population, results for only the prespecified analysis population {SABER-Bupivacaine (Part 1 and Part 2 combined) and Bupivacaine HCl (Part 2)} are provided, there was no prespecified secondary outcome measure that included the Saline Placebo (Part 1) arm or the SABER-Bupivacaine (Part 1) arm as a standalone treatment group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2/SABER-Bupivacaine | Total IV Morphine-equivalent Dose of Rescue Opioids | 21.4 IV morphine equivalent (mg) | Standard Error 1.37 |
| Part 2/Bupivacaine HCl | Total IV Morphine-equivalent Dose of Rescue Opioids | 22.6 IV morphine equivalent (mg) | Standard Error 1.58 |