Phase 3 Study of Efficacy and Safety of the XaraColl® Bupivacaine Implant After Hernioplasty

Study Overview
=================
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).

Official Title
-----------------
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of the XaraColl® Bupivacaine Implant (300 mg Bupivacaine Hydrochloride) After Open Laparotomy Hernioplasty

Conditions
-----------------
Pain, Postoperative

Intervention / Treatment
-----------------
* Drug: XaraColl
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XaraColl<br>3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose | Drug: XaraColl<br>* Surgical implantation of 3 bupivacaine collagen implants<br>* Other names: Bupivacaine collagen implant;|
| Placebo Comparator: Placebo<br>3 placebo implants | Other: Placebo<br>* Plain collagen implant (vehicle)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SPI24 | Sum of Pain Intensity (SPI24). The time weighted sum of pain intensity from 0 to 24 hours (ie, the area under the NRS PI curve from 0 to 24 hours). Where 0 indicated no pain and 10 indicated worst pain possible. This type of measurement scale is called NRS or Numerical Rating Scale For the purpose of (SPI) computation, PI at Time 0 (Baseline PI) is set to zero for all patients who have test article implantation. SPI will not be calculated for randomized but not treated patients. A lower score is a better outcome. 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. | 0 to 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 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 0 through 24 hours | 
| TOpA48 | Total use of Opioid Analgesia 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 0 through 48 hours | 
| TOpA72 | Total use of Opioid Analgesia (TOpA) from Time 0 through 72 hours. This is a basic measurement of counting in total the number of morphine tablets 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 0 through 72 hours | 
| SPI48 | Sum of pain intensity (SPI).The time weighted sum of pain intensity from 0 to 48 hours (ie, the area under the NRS PI curve from 0 to 48 hours). For the purpose of SPI computation, Pain Intensity at Time 0 (Baseline PI) is set to zero for all patients who have test article implantation. 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 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. | 0 to 48 hours | 
| SPI72 | Sum of pain intensity (SPI). The time weighted sum of pain intensity from 0 to 72 hours (ie, the area under the NRS PI curve from 0 to 72 hours). For the purpose of SPI computation, PI at Time 0 (Baseline PI) is set to zero for all patients who have test article implantation. Where 0 indicates no pain and 10 indicated worst pain possible. A lower score is a better outcome. 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. | 0 to 72 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
post operative pain, hernioplasty, bupivacaine