Pain, Postoperative
Conditions
Keywords
post operative pain, hernioplasty, bupivacaine
Brief summary
This is a Phase 3, multicenter, randomized, double-blind, parallel-group, placebo-controlled efficacy and safety study of postoperative pain in adults who are scheduled for unilateral inguinal hernioplasty via open laparotomy (tension-free technique). Patients will assess their postoperative pain intensity (PI) using an 11-point numerical rating scale (NRS) from 0 hour through 72 hours postoperatively. The expected maximum study duration for each patient will be up to 60 days, including a maximum 30-day screening period, the day of surgery and implantation, and a 30-day post implantation period including treatment and follow-up.
Detailed description
This is a Phase 3, multicenter, randomized, double-blind, parallel-group, placebo-controlled study in adults who are scheduled for unilateral inguinal hernioplasty via open laparotomy (tension-free technique). Patients will receive either 3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose; or 3 placebo-sponges. Three test article sponges will be implanted according to the patient's blinded treatment assignment. Following surgery, patients will be transferred to a postanesthesia care unit (PACU) and/or other postoperative recovery area for observation where they may receive parenteral morphine as needed (rescue medication for breakthrough pain) and on request for pain control. Once patients can tolerate oral medication, they will commence a standardized oral analgesic regimen with additional PRN medication to manage breakthrough pain only when it occurs. Patients will assess their postoperative pain intensity (PI) using an 11-point numerical rating scale (NRS) from 0 hour through 72 hours postoperatively. Patients will be observed postoperatively for a minimum of 3 hours and may be discharged at any time following completion of their 3-hour vital sign and PI assessments. Patients will be contacted at approximately 6, 24 and 48 hours after implantation to ensure protocol compliance and to perform safety assessments (including AEs and concomitant medications). At 72 hours, patients will return to the clinic to perform their final PI assessment, complete a categorical assessment of their overall pain control, and for follow-up safety assessments. They will also be asked to record the incidence of any ongoing or subsequent AEs (and any associated treatment) through Day 7. Additional follow-up assessments for safety will be performed at postoperative Day 7 (telephone call) and Days 15 and 30 (clinic visits).
Interventions
DRUGXaraColl
Surgical implantation of 3 bupivacaine collagen implants
OTHERPlacebo
Plain collagen implant (vehicle)
Sponsors
Innocoll
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
* Has a planned (non-emergent) unilateral inguinal hernioplasty (open laparotomy, tension-free technique) to be performed according to standard surgical technique under general anesthesia. Repair of multiple hernias through a single incision is permitted provided only a single mesh will be used. * If female, is nonpregnant and nonlactating. * If female, is either not of childbearing potential (defined as postmenopausal for ≥ 1 year or surgically sterile \[bilateral tubal ligation, bilateral oophorectomy or hysterectomy\]) or practicing 1 of the protocol specified medically-acceptable methods of birth control and agrees to continue with the regimen throughout the duration of the study: * Has the ability and willingness to comply with the study procedures and use of the eDiary. * Is willing to use only permitted medications throughout the study. * Is willing to use opioid analgesia. * Must be able to fluently speak and understand either English or Spanish and be able to provide meaningful written informed consent for the study.
Exclusion criteria
* Has a known hypersensitivity to amide local anesthetics, morphine, acetaminophen or bovine products. * Is scheduled for bilateral inguinal hernioplasty or other significant concurrent surgical procedures per investigator discretion. * Has undergone major surgery within 3 months of the scheduled hernioplasty or plans to undergo another laparotomy procedure within 30 days postoperatively. * Has used any analgesic other than acetaminophen within 24 hours of surgery. Acetaminophen may be used on the day of surgery but is subject to preoperative restrictions for oral intake. * Has used aspirin or aspirin-containing products within 7 days of surgery. Aspirin at a dose of ≤ 325 mg is allowed for cardiovascular prophylaxis if the patient has been on a stable dose regimen for ≥ 30 days before Screening. * Has used systemic steroids, anticonvulsants, antiepileptics, antidepressants for the management of chronic pain, or monoamine oxidase inhibitors on a regular basis within 10 days of surgery. * Has used any opioid analgesic for an extended daily basis (30 - 60 mg oral morphine equivalent per day for 3 or more days a week) within 4 weeks before surgery. Patients who, in the investigator's opinion, may be developing opioid tolerance are also excluded. * Has any chronic painful condition (eg, fibromyalgia) or routinely uses pain medication other than acetaminophen (including nonsteroidal anti-inflammatory drugs \[NSAIDs\]) that, in the opinion of the investigator, may confound the assessment of pain associated with the hernioplasty. * Has a physical or mental condition that, in the opinion of the investigator, may confound the assessment of postoperative pain after hernioplasty. * Shows evidence of tolerance or physical dependency on opioid analgesics or sedative-hypnotic medications. * Has a urine drug screen that tests positive for drugs of abuse or misuse, including cannabinoids. * Has liver function test results greater than 3x the upper limit of normal or a history of cirrhosis. * Has any clinically significant unstable cardiac disease (eg, uncontrolled hypertension, clinically significant arrhythmia at baseline, or an implantable cardioverter-defibrillator \[ICD\]) * Has any clinically significant unstable neurological, immunological, renal, or hematological disease (eg, uncontrolled diabetes or significantly abnormal laboratory findings), or any other condition that, in the opinion of the investigator, could compromise the patient's welfare, ability to communicate with the study staff or otherwise contraindicate study participation. * Has an open workman's compensation claim. * Has participated in a clinical trial (investigational or marketed product) within 30 days of surgery.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SPI24 | 0 to 24 hours | The primary efficacy variable (time-weighted sum of pain intensity from Time 0 through 24 hours \[SPI24\]) was compared once at a 2-sided 0.05 level. Therefore, no multiplicity adjustment was necessary for the primary efficacy analysis. Pain Intensity was assessed by the subject using the 11-point NRS, where 0 indicated no pain and 10 indicated worst pain possible. Minimum value would be 0 and Maximum value would be 240. Time-weighted SPI is calculated as the sum of the pain intensities between successive time points (i.e., if SPI24 = ∑\[PI x (time t - time t-1)\], where t represents a given time point,t-1 represents the previous time point, and time is expressed in hours). This represents the AUC (Area Under the Curve) of the pain intensities when calculated with the trapezoidal rule. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| TOpA24 | Time 0 through 24 hours | Total use of opioid analgesia (TOpA) from Time 0 through 24 hours (TOpA24) This is a basic measurement of counting in total the number of morphine tablets (15 mg) patients had to use within a 24-hour period (typically called rescue to help manage pain. Zero (0) is the lowest score. The lower the number of tablets the better outcome. |
| TOpA48 | Time 0 through 48 hours | Total use of opioid analgesia (TOpA) from Time 0 through 48 hours (TOpA48) This is a basic measurement of counting in total the number of morphine tablets (15 mg) patients had use within a 48-hour period (typically called rescue to help manage pain. Zero (0) is the lowest score. The lower the number of tablets the better outcome. |
| TOpA72 | Time 0 through 72 hours | Total use of opioid analgesia (TOpA) from Time 0 through 72 hours (TOpA72) This is a basic measurement of counting in total the number of morphine tablets (15 mg) patients had use within a 72-hour period (typically called rescue to help manage pain. Zero (0) is the lowest score. The lower the number of tablets the better outcome. |
| SPI48 | 0 to 48 hours | Time-weighted sum of pain intensity from Time 0 through 48 hours (SPI48). Lower score has a better outcome. Pain Intensity was assessed by the subject using the 11-point NRS, where 0 indicated no pain and 10 indicated worst pain possible. Minimum value would be 0 and Maximum value would be 480. Time-weighted SPI is calculated as the sum of the pain intensities between successive time points (i.e., if SPI48 = ∑\[PI x (time t - time t-1)\], where t represents a given time point,t-1 represents the previous time point, and time is expressed in hours). This represents the AUC (Area Under the Curve) of the pain intensities when calculated with the trapezoidal rule. |
| SPI72 | 0 to 72 hours | Time-weighted sum of pain intensity from Time 0 through 72 hours (SPI72) A lower score is a better outcome. Pain Intensity was assessed by the subject using the 11-point NRS, where 0 indicated no pain and 10 indicated worst pain possible Minimum value would be 0 and Maximum value would be 720. Time-weighted SPI is calculated as the sum of the pain intensities between successive time points (i.e., if SPI72 = ∑\[PI x (time t - time t-1)\], where t represents a given time point,t-1 represents the previous time point, and time is expressed in hours). This represents the AUC (Area Under the Curve) of the pain intensities when calculated with the trapezoidal rule. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| XaraColl 3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose
XaraColl: Surgical implantation of 3 bupivacaine collagen implants | 207 |
| Placebo 3 placebo implants
Placebo: Plain collagen implant (vehicle) | 105 |
| Total | 312 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 0 | 1 |
| Overall Study | did not meet randomization criteria | 1 | 0 |
| Overall Study | Lost to Follow-up | 5 | 1 |
| Overall Study | randomized not enrolled | 3 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | XaraColl | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 50.7 years STANDARD_DEVIATION 13.69 | 48.5 years STANDARD_DEVIATION 13.84 | 50.0 years STANDARD_DEVIATION 13.79 |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 202 Participants | 102 Participants | 304 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 208 | 1 / 107 |
| other Total, other adverse events | 118 / 208 | 76 / 107 |
| serious Total, serious adverse events | 3 / 208 | 3 / 107 |
Outcome results
Primary
SPI24
The primary efficacy variable (time-weighted sum of pain intensity from Time 0 through 24 hours \[SPI24\]) was compared once at a 2-sided 0.05 level. Therefore, no multiplicity adjustment was necessary for the primary efficacy analysis. Pain Intensity was assessed by the subject using the 11-point NRS, where 0 indicated no pain and 10 indicated worst pain possible. Minimum value would be 0 and Maximum value would be 240. Time-weighted SPI is calculated as the sum of the pain intensities between successive time points (i.e., if SPI24 = ∑\[PI x (time t - time t-1)\], where t represents a given time point,t-1 represents the previous time point, and time is expressed in hours). This represents the AUC (Area Under the Curve) of the pain intensities when calculated with the trapezoidal rule.
Time frame: 0 to 24 hours
Population: modified intent-to-treat - The mITT population consisted of randomized subjects who received any dose of INL-001 or placebo and who had at least 1 NRS PI score prior to hospital discharge, as needed, to compute SPI.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| XaraColl | SPI24 | 88.3 units on a scale | Standard Deviation 47.01 |
| Placebo | SPI24 | 116.2 units on a scale | Standard Deviation 44.04 |
Secondary
SPI48
Time-weighted sum of pain intensity from Time 0 through 48 hours (SPI48). Lower score has a better outcome. Pain Intensity was assessed by the subject using the 11-point NRS, where 0 indicated no pain and 10 indicated worst pain possible. Minimum value would be 0 and Maximum value would be 480. Time-weighted SPI is calculated as the sum of the pain intensities between successive time points (i.e., if SPI48 = ∑\[PI x (time t - time t-1)\], where t represents a given time point,t-1 represents the previous time point, and time is expressed in hours). This represents the AUC (Area Under the Curve) of the pain intensities when calculated with the trapezoidal rule.
Time frame: 0 to 48 hours
Population: (mITT Population)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| XaraColl | SPI48 | 188.1 units on a scale |
| Placebo | SPI48 | 214.9 units on a scale |
Secondary
SPI72
Time-weighted sum of pain intensity from Time 0 through 72 hours (SPI72) A lower score is a better outcome. Pain Intensity was assessed by the subject using the 11-point NRS, where 0 indicated no pain and 10 indicated worst pain possible Minimum value would be 0 and Maximum value would be 720. Time-weighted SPI is calculated as the sum of the pain intensities between successive time points (i.e., if SPI72 = ∑\[PI x (time t - time t-1)\], where t represents a given time point,t-1 represents the previous time point, and time is expressed in hours). This represents the AUC (Area Under the Curve) of the pain intensities when calculated with the trapezoidal rule.
Time frame: 0 to 72 hours
Population: mITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| XaraColl | SPI72 | 264.5 units on a scale |
| Placebo | SPI72 | 299.7 units on a scale |
Secondary
TOpA24
Total use of opioid analgesia (TOpA) from Time 0 through 24 hours (TOpA24) This is a basic measurement of counting in total the number of morphine tablets (15 mg) patients had to use within a 24-hour period (typically called rescue to help manage pain. Zero (0) is the lowest score. The lower the number of tablets the better outcome.
Time frame: Time 0 through 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| XaraColl | TOpA24 | 5.0 morphine equivalents |
| Placebo | TOpA24 | 14 morphine equivalents |
Secondary
TOpA48
Total use of opioid analgesia (TOpA) from Time 0 through 48 hours (TOpA48) This is a basic measurement of counting in total the number of morphine tablets (15 mg) patients had use within a 48-hour period (typically called rescue to help manage pain. Zero (0) is the lowest score. The lower the number of tablets the better outcome.
Time frame: Time 0 through 48 hours
Population: mITT Population)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| XaraColl | TOpA48 | 5 morphine equivalent |
| Placebo | TOpA48 | 14 morphine equivalent |
Secondary
TOpA72
Total use of opioid analgesia (TOpA) from Time 0 through 72 hours (TOpA72) This is a basic measurement of counting in total the number of morphine tablets (15 mg) patients had use within a 72-hour period (typically called rescue to help manage pain. Zero (0) is the lowest score. The lower the number of tablets the better outcome.
Time frame: Time 0 through 72 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| XaraColl | TOpA72 | 10 morphine tablets |
| Placebo | TOpA72 | 20 morphine tablets |