Pharmacokinetics, Relative Bioavailability and Safety of INL-001 Compared to Marcaine After Open Hernioplasty

Study Overview
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Brief Summary
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This is a multicenter randomized, single-blind, controlled study. The primary objectives of this study are to obtain the pharmacokinetic profile and the relative bioavailability of the INL-001 matrix during and after open hernioplasty compared to Marcaine™ 0.25% infiltration.

Detailed Description
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This is a multicenter randomized, single-blind, controlled study. Prior to surgery on Day 1, 48 subjects who continue to meet study entry criteria will be randomized just prior to surgery in a 2:1 ratio to receive either 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg) or Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration. Subjects will then undergo open hernioplasty according to standard procedure. Subjects will remain in the clinic at least until after the 72 hour blood sample has been collected for PK analysis on Day 4. Subjects discharged after the 72 hour blood draw will be instructed to return to the clinic to complete the 96 hour PK blood draw on Day 5. Follow-up safety assessments will include clinic visits on Day 7, Day 15 and Day 30. Pharmacokinetic blood samples will be collected from subjects before surgery and at predetermined time points up to 96 hours after administration of study drug. Safety assessments will include frequent assessment of vital signs through 72 hours, continuous electrocardiogram (ECG) monitoring for at least 24 hours, oxygen saturation levels, and adverse events (AEs) reporting with particular emphasis on the signs and symptoms of CNS and cardiovascular bupivacaine toxicity. The surgical wound will be assessed frequently for adverse events associated with altered wound healing.

Official Title
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A Randomized, Single Blind Study to Investigate the PK, Relative Bioavailability and Safety of INL-001 Bupivacaine HCl Collagen-Matrix Implant 300 mg Compared to Marcaine™ 0.25% (Bupivacaine HCl) 175 mg Infiltration After Open Hernioplasty

Conditions
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Hernioplasty

Intervention / Treatment
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* Combination Product: INL-001 (bupivacaine HCl collagen implant)
* Drug: Marcaine 0.25% infiltration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for inclusion into the study, subjects must: Be a man or woman ≥18 years of age. Be eligible for unilateral inguinal hernioplasty with mesh (open laparotomy, tension-free technique) performed according to standard surgical technique under general anesthesia. Repair of multiple hernias through a single incision is permitted. If female of childbearing potential, have a negative pregnancy test at screening and before randomization on Day 1 AND be using an effective contraception method (ie, abstinence, intrauterine device [IUD], hormonal [estrogen/progestin] contraceptives, or barrier control) for at least one menstrual cycle prior to study enrollment and for the duration of the study, OR be surgically sterile, OR be a postmenopausal female (no menses for at least 1 year or hysterectomy). Has the ability and willingness to comply with the study procedures. Be willing to use only permitted medications throughout the study. Be willing to use opioid analgesia. 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: A subject will be excluded from study participation if prior to surgery he/she: Has a known hypersensitivity to amide local anesthetics, morphine, acetaminophen, or bovine products. Is scheduled for bilateral inguinal hernioplasty or other significant concomitant surgical procedure. Has undergone major surgery within 3 months of the scheduled hernioplasty or plans to undergo another laparotomy procedure within the 30 day postoperative period. 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 any clinically significant unstable cardiac, neurological, immunological, renal, hepatic or hematological disease or any other condition that, in the opinion of the investigator, could compromise the subject's welfare, ability to communicate with the study staff or otherwise contraindicate study participation. Has venous access difficulties that may preclude the frequent pharmacokinetic sampling requirements of the study. Has participated in a clinical trial (investigational or marketed product) 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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All

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INL-001<br>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg. | Combination Product: INL-001 (bupivacaine HCl collagen implant)<br>* 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)<br>* Other names: INL-001;|
| Active Comparator: Marcaine 0.25% infiltration<br>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg). | Drug: Marcaine 0.25% infiltration<br>* Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration<br>* Other names: Marcaine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Maximum (peak) plasma concentration | 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours. | 
| Tmax | Time to maximum (peak) plasma concentration | 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours | 
| Tlag | Lag-time | 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours | 
| t½ Terminal Half Life | Terminal half-life | 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours | 
| λz | Terminal phase rate constant | 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours | 
| AUC | Area under the plasma concentration-time curve from Time 0 to last time of last quantifiable plasma concentration (AUC0-last) | 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours | 
| AUC0-∞ | AUC from Time 0 to infinity | 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours | 
| AUC Extrapolated | AUC = area under the plasma concentration-time curve; | 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Bioavailability, Safety, Bupivacaine, Collagen, Implant, Marcaine, Hernioplasty