Efficacy, Safety and Pharmacokinetic Profile of a Collagen Bupivacaine Implant in Men After Open Mesh Herniorrhaphy

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the CollaRx Bupivacaine implant is safe and effective in reducing the amount of narcotic pain medication needed to control pain during the first 24 hours after herniorrhaphy.

Detailed Description
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Inguinal herniorrhaphy is a common surgery; and common surgical methods used include laparoscopic and open placement of synthetic mesh. The use of synthetic mesh can greatly reduce the risk of hernia recurrence regardless of the method used for its placement. Managing postoperative pain and preventing morbidity after open mesh herniorrhaphy remain considerable medical challenges. Bupivacaine is a local anesthetic (pain medicine) that has an established safety profile. Collagen is a protein that is found in all mammals. The CollaRx Bupivacaine implant is a thin flat sponge made out of collagen that comes from cow tendons and contains bupivacaine. When inserted into a surgical site, the collagen breaks down and bupivacaine is released at the site but very little is absorbed into the blood stream. The high levels of bupivacaine at the surgical site may result in less pain for several days after surgery. This study will compare the amount of narcotic pain medication required after surgery in patients who receive either the CollaRx Bupivacaine implant or a plain collagen sponge.

Official Title
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A Phase II, Randomized, Single Dose, Double-blind, Placebo-controlled Study to Investigate the Efficacy, Safety and Pharmacokinetic Profile of the CollaRx® Bupivacaine Implant in Men After Open Mesh Herniorrhaphy

Conditions
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Postoperative Pain, Inguinal Hernia

Intervention / Treatment
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* Drug: Bupivacaine Collagen Sponge
* Drug: placebo collagen sponge


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has body mass index (BMI) > 19 and < 40 kg/m2. Has a planned unilateral inguinal herniorrhaphy (open mesh, tension free technique) to be performed according to standard surgical technique under general anesthesia. Has a risk classification of I, II or III according to the ASA. Is free of other physical or mental conditions that, in the opinion of the Investigator, may confound the quantification of postoperative pain after herniorrhaphy. Has the ability and willingness to comply with the study procedures and the use of the pain scales. Is willing to use only permitted medications and anesthetics throughout the study. Is willing to use opioid rescue analgesia for moderate to severe incisional pain only. Must voluntarily sign and date an informed consent form (ICF) that is approved by an Institutional Review Board (IRB) before the conduct of any study specific procedures. Must be able to fluently speak and understand English and be able to provide meaningful written informed consent for the study. Exclusion Criteria: Has a known hypersensitivity to amide local anesthetics, opioids, bovine products or inactive ingredients of the test article. Is scheduled for bilateral inguinal herniorrhaphy. Has undergone a prior herniorrhaphy on the side that is currently scheduled for repair. Has cardiac arrhythmias or atrioventricular (AV) conduction disorders. Concomitantly uses antiarrhythmics (eg, amiodarone), propranolol or strong/moderate cytochrome P450 (CYP) 3A4 inhibitors or inducers (eg, macrolide antibiotics and grapefruit juice). Has used long acting analgesics within 24 hours of surgery. Short acting analgesics such as acetaminophen may be used on the day of surgery 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 undergone major surgery within 3 months of the scheduled herniorrhaphy. Has known or suspected history of alcohol or drug abuse or misuse within 3 years of Screening or evidence of tolerance or physical dependency on opioid analgesics or sedative-hypnotic medications. Has used opioids or tramadol on an extended daily basis (> 7 days) before surgery. Patients who, in the Investigator's opinion, are developing opioid tolerance are to be excluded. Has impaired liver function, aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin ≥ 3.0 times the upper limit of normal (ULN), active hepatic disease, evidence of clinically significant liver disease or another condition (eg, alcoholism, cirrhosis or hepatitis) that may suggest the potential for an increased susceptibility to hepatic toxicity with exposure to test article. Has any clinically significant unstable cardiac, neurological, immunological, renal or hematological disease 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. Is judged by the Investigator to be at risk for infection or slow wound healing. Has a chronic painful condition that might confound the assessment of pain associated with the herniorrhaphy. Routinely uses pain medication that, in the opinion of the Investigator, could confound the pain assessments during the study. Has been treated with agents that could affect the analgesic response (such as central alpha agents, neuroleptic agents and other antipsychotic agents) within 2 weeks of surgery. Has been treated with monoamine oxidase inhibitors (MAOIs) within 10 days of surgery. Has been treated with systemic corticosteroids within 7 days of surgery (inhaled and topical corticosteroids are allowed). Has participated in a clinical trial within 30 days of surgery.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Two, 5x5cm bupivacaine collagen sponges implanted during surgery | Drug: Bupivacaine Collagen Sponge<br>* collagen; Bupivacaine hydrocholoride<br>* Other names: CollaRx Bupivacaine Implant;|
| Placebo Comparator: 2<br>Placebo collagen sponge implanted during surgery | Drug: placebo collagen sponge<br>* collagen<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Use of Opioid Rescue Analgesia Over 0 to 24 Hours | Total Use of Opioid Rescue Analgesia (mg) Over 0 to 24 Hour - number count - higher score means worse outcome | 0 to 24 hours postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Use of Opioid Rescue Analgesia Over 0 to 48 Hours | Number count. Higher score means worse outcome | 0 to 48 hours postoperatively | 
| Total Use of Opioid Rescue Analgesia Over 0 to 72 Hours | Number count - higher score means worse outcome | 0 to 72 hours postoperatively | 
| Summed Pain Intensity VAS Scores (VAS at Rest and After Cough) | Summed pain intensity (SPI) (VAS at rest and after cough): - For the VAS assessment, patients measured their pain intensity at rest and after aggravated movement (cough) using a horizontal 100-mm VAS scale labeled as follows: No Pain (0 mm) as the left anchor and Worst Pain Imaginable (100 mm) as the right anchor. Each timepoint consist of two measurements (Resting & Coughing) - The lower the score the better outcome for the patient. The highest total score (worst possible score) for the 10 timepoints would be 2000. | 1, 1.5, 2, 3, 4, 5, 6, 24, 48 and 72 hours after Time 0 | 
| Patient's Global Evaluation of the Study Treatment on a 5 Point Likert Scale | For the 5-point categorical scale global evaluation of study treatment, the patient was instructed to score his global evaluation of the pain control provided by the study treatment where: 0 = poor, 1 = fair, 2 = good, 3 = very good and 4 = excellent | At 72 hours after time 0 | 
| VAS Pain Intensity Scores Over Time | For the VAS assessment, patients measured their pain intensity at rest and after aggravated movement (cough) using a horizontal 100-mm VAS scale labeled as follows: No Pain (0 mm) as the left anchor and Worst Pain Imaginable (100 mm) as the right anchor. | At 1, 1.5, 2,3,4,5,6,24,48,72 Hours | 
| Categorical Pain Intensity Scores Over Time - AT REST | For the 4-point categorical scale assessment, patients measured their pain intensity at rest and after aggravated movement (cough) using a numerical scale where: 0 = none, 1 = mild, 2 = moderate and 3 = severe. | At 0.5, 1, 1.5, 2, 3, 4, 5, 6, 24, 48 and 72 hours | 
| Categorical Pain Relief Scores Over Time - AT REST | For the 5-point categorical scale assessment of pain relief, the patient was instructed to score his pain relief using a numerical scale where: 0 = no relief, 1 = a little relief, 2 = some relief, 3 = a lot of relief and 4 = complete relief. | At 0.5, 1, 1.5, 2, 3, 4, 5, 6, 24, 48 and 72 hours | 
| Categorical Pain Intensity Scores Over Time (After Cough) | For the 4-point categorical scale assessment, patients measured their pain intensity at rest and after aggravated movement (cough) using a numerical scale where: 0 = none, 1 = mild, 2 = moderate and 3 = severe. Higher Score means a worse outcome | At 0.5, 1, 1.5, 2, 3, 4, 5, 6, 24, 48 and 72 hours | 
| Categorical Pain Relief Scores Over Time (After Cough) | For the 5-point categorical scale assessment of pain relief, the patient was instructed to score his pain relief using a numerical scale where: 0 = no relief, 1 = a little relief, 2 = some relief, 3 = a lot of relief and 4 = complete relief. | At 0.5, 1, 1.5, 2, 3, 4, 5, 6, 24, 48 and 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Herniorrhaphy, Inguinal Hernia Repair, Postoperative pain