Ignite Creation Date:
2024-05-05 @ 11:29 PM
Last Modification Date:
2024-10-26 @ 10:35 AM
Study NCT ID:
NCT01349140
Status:
COMPLETED
Last Update Posted:
2021-03-25
First Post:
2011-05-04
Brief Title:
EXPAREL Dose-Response for Single-Injection Femoral Nerve Blocks
Sponsor:
University of California San Diego
Organization:
University of California San Diego
Study Overview
Official Title:
EXPAREL Dose-Response for Single-Injection Femoral Nerve Blocks A Pharmacodynamics Investigation in Healthy Volunteers
Status:
COMPLETED
Status Verified Date:
2021-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
EXPAREL an investigational drug product is a new formulation of a local anesthetic numbing medicine that is designed to be longer acting than the currently-available local anesthetics The purpose of this study is to define the dose-response curve of EXPAREL an investigational extended-duration formulation of the local anesthetic bupivacaine on both motor and sensory block when applied in a fixed volume adjacent to the femoral nerve
Detailed Description:
Putting local anesthetic next to a nerve is a common way of decreasing the pain that patients feel after surgery For knee surgery the local anesthetic is placed next to the femoral nerve in the middle of the crease where the leg meets the body when bending at the hip joint However the local anesthetic takes away not only sensation-and therefore pain-but also motor control leaving muscles weaker It would greatly improve patient safety if the investigators could administer a very long-acting local anesthetic that decreased postoperative pain but affected muscle strength only minimally The purpose of this study is to define the dose-response curve of EXPAREL also termed SKY0402 an investigational extended-duration formulation of the local anesthetic bupivacaine on both motor and sensory block when applied in a fixed volume adjacent to the femoral nerve
This investigation will be a Phase 1 prospective double-masked human-subjects dose-response clinical trial
Enrollment Subjects will be volunteers of both sexes age 18 and older If a volunteer meets inclusionexclusion criteria and desires study participation written informed consent will be obtained Selection for inclusion will not be based on race or socioeconomic status The study population of interest includes men and women of all races and socioeconomic status
Subject preparation Following written informed consent subjects will be admitted to the UCSD CTRI and have demographicmorphometric data recorded eg age weight height a medical history recorded and a brief physical examination Block placement itself may occur either in the UCSD CTRI or Hillcrest Outpatient Surgical Center Post Anesthesia Care Unit PACU this is where regional anesthetics are administered on a regular basis for surgical patients If the blocks are placed in the PACU subjects will remain there for two hours and then moved accompanied by a physician on their gurney to the UCSD CTRI where they will spend the remainder of the study period Women of childbearing potential will have a urine pregnancy test Prior to dosing baseline quadriceps strength and sensory level measurements will also be obtained An intravenous line will be placed in an upper extremity followed by external monitors pulse oximeter blood pressure and EKG and oxygen by nasal cannula 1-6 Lmin Sedation will be provided by a combination of one or more of the following titrated to effect oral valium 10 mg intravenous fentanyl 50 mcg andor intravenous midazolam 1 mg Following sterile preparation with chlorhexidine gluconate and isopropyl alcohol and once the topical antiseptic is dry subjects will have bilateral single-injection ultrasound-guided femoral nerve blocks placed using standard UC San Diego techniques as previously published by the current PI
Treatment Group Assignment The dominant side left or right will be randomized to one of two treatment groups the higher or lower concentration of the local anesthetic SKY0402 The non-dominant contralateral side will receive the other possible treatment The volume of each and every single-injection femoral nerve block will be 30 mL standard for femoral nerve blocks is 30-40 mL Since volume will remain constant we will vary the dose of SKY0402 by varying concentration volume x concentration dose Of note SKY0402 may be mixed with normal saline to vary the concentration Randomization will be based on computer-generated codes Randomization will be in blocks of two
Dose Determination Initial doses of SKY0402 will begin at 0 mg low exclusively normal saline as the treatment and 2 mg high for the first subject and 1 mg low and 3 mg high for the second subject Since the volume of each of the bilateral blocks will be 30 mL the first subjects concentrations will be 0 mg 30 mL 0 and 2 mg 30 mL 0007 while the second subjects concentrations will be 1 mg 30 mL 0003 and 3 mg 30 mL 0010 Unmasking of treatments will occur following data collection for each subject to allow determination of dosing for subsequent subjects The subsequent doses will be between 0-160 mg 0534 per side determined prior to randomization of each subsequent subject The specific subsequent doses will increase remain the same or decrease determined by the PI in consultation with the manufacturer of SKY0402 Since the dose-response for SKY0402 remains unknown for single-injection peripheral nerve blocks a set tier or dose-increase plan prior to experience with each subject is impossible However the dose will never be increased by more than 20 mg for each side In addition doses will always remain within the range of 0-160 mg 0 - 0534 per side and never exceed a total dose of 160 mg for both sides combined Dose escalation will be stopped and only lower doses will be administered subsequently if either of the following occurs after study drug administration one subject experiences clinically significant motor block persisting more than 7 days or four consecutive subjects experience clinically significant motor block persisting more than 5 days
For unsuccessful local anesthetic deposition defined as local anesthetic that could not be deposited immediately adjacent to the femoral nerve as viewed by real-time ultrasound or subject withdrawal from the study the subjects data will not be included in the analysis and the subject dropped from the study subjects will always receive compensation for at least one night in the CTRI--400-even if they are discharged the day of block placement due to failed deposition Remaining subjects will remain within the CTRI and within their bed until discharged home Discharge will occur when quadriceps strength has returned to at least 80 of its baseline value We consider a difference of less than 20 percentage points to be clinically relevant because a 10 side-to-side strength difference is common yet functionally unnoticeable in healthy individuals45 Discharge will occur-at the very earliest-24 hours following initial block placement Therefore the amount of time subjects will spend in the CTRI will depend upon the duration of local anesthetic action which will be variable among subjects and is currently unpredictable without a dose-response curve for peripheral nerve blocks using SKY0402 We anticipate the duration of study participation for each subject to be approximately 72 hours Subjects may withdraw from participation at any time and will receive compensation for the time they have participated up until withdrawal subjects who withdraw the day of block placement will receive 400 However if the research coordinator who is responsible for distributing the compensation is not available at the time of study withdrawal then the subject will need to return to the CTRI the following day or following Monday if withdrawal occurs over the weekend for compensation
Outcome Measurements We have selected measures that have established reliability and validity Staff blinded to treatment group assignment will perform all measures and assessments For all measurements the dominant side will always be tested first followed by the contralateral side Measurements will be performed prior to local anesthetic administration initiation baseline Hour 0 as well as specific post-block time points
Hour Prior to Hour 0 0 010 020 030 040 050
1 115 130 145 2 230 3 330 4 5 6 7 8 9 10 24 Day 2 27-36 48 Day 3 51-60 72 Day 4 75-84 96 Day 5 99-108 120 Day 6
Primary Outcome Measurement
Quadriceps femoris muscle strength Evaluated using a portable isometric force dynamometer to measure the maximum voluntary isometric contraction MVIC in a seated position with the knee flexed at 90ยบ This variable will be presented and analyzed as post pre x 100 For all measurements subjects will be asked to take 2 sec to come to maximum effort contracting the target muscles maintain this effort for 5 sec and then relax
Secondary Outcome Measurement
Sensory level Evaluated using transcutaneous electrical stimulation TES in the same manner as described throughout the anesthesia literature this is a gold standard for regional anesthesia studies After clipping any hair EKG pads will be positioned 2 cm medial to the proximal patella and quadriceps tendon and attached to a nerve stimulator The current will be increased from 0 mA until the subject identifies slight discomfort at which time the current is recorded as the TES value and the nerve stimulator turned off The secondary end point will be the post-administration maximum current absolute values in mA
Safety Assessments Safety assessments will include monitoring of AEs SAEs and vital signs heart rate respiratory rate and blood pressure
This investigation will be a Phase 1 prospective double-masked human-subjects dose-response clinical trial
Enrollment Subjects will be volunteers of both sexes age 18 and older If a volunteer meets inclusionexclusion criteria and desires study participation written informed consent will be obtained Selection for inclusion will not be based on race or socioeconomic status The study population of interest includes men and women of all races and socioeconomic status
Subject preparation Following written informed consent subjects will be admitted to the UCSD CTRI and have demographicmorphometric data recorded eg age weight height a medical history recorded and a brief physical examination Block placement itself may occur either in the UCSD CTRI or Hillcrest Outpatient Surgical Center Post Anesthesia Care Unit PACU this is where regional anesthetics are administered on a regular basis for surgical patients If the blocks are placed in the PACU subjects will remain there for two hours and then moved accompanied by a physician on their gurney to the UCSD CTRI where they will spend the remainder of the study period Women of childbearing potential will have a urine pregnancy test Prior to dosing baseline quadriceps strength and sensory level measurements will also be obtained An intravenous line will be placed in an upper extremity followed by external monitors pulse oximeter blood pressure and EKG and oxygen by nasal cannula 1-6 Lmin Sedation will be provided by a combination of one or more of the following titrated to effect oral valium 10 mg intravenous fentanyl 50 mcg andor intravenous midazolam 1 mg Following sterile preparation with chlorhexidine gluconate and isopropyl alcohol and once the topical antiseptic is dry subjects will have bilateral single-injection ultrasound-guided femoral nerve blocks placed using standard UC San Diego techniques as previously published by the current PI
Treatment Group Assignment The dominant side left or right will be randomized to one of two treatment groups the higher or lower concentration of the local anesthetic SKY0402 The non-dominant contralateral side will receive the other possible treatment The volume of each and every single-injection femoral nerve block will be 30 mL standard for femoral nerve blocks is 30-40 mL Since volume will remain constant we will vary the dose of SKY0402 by varying concentration volume x concentration dose Of note SKY0402 may be mixed with normal saline to vary the concentration Randomization will be based on computer-generated codes Randomization will be in blocks of two
Dose Determination Initial doses of SKY0402 will begin at 0 mg low exclusively normal saline as the treatment and 2 mg high for the first subject and 1 mg low and 3 mg high for the second subject Since the volume of each of the bilateral blocks will be 30 mL the first subjects concentrations will be 0 mg 30 mL 0 and 2 mg 30 mL 0007 while the second subjects concentrations will be 1 mg 30 mL 0003 and 3 mg 30 mL 0010 Unmasking of treatments will occur following data collection for each subject to allow determination of dosing for subsequent subjects The subsequent doses will be between 0-160 mg 0534 per side determined prior to randomization of each subsequent subject The specific subsequent doses will increase remain the same or decrease determined by the PI in consultation with the manufacturer of SKY0402 Since the dose-response for SKY0402 remains unknown for single-injection peripheral nerve blocks a set tier or dose-increase plan prior to experience with each subject is impossible However the dose will never be increased by more than 20 mg for each side In addition doses will always remain within the range of 0-160 mg 0 - 0534 per side and never exceed a total dose of 160 mg for both sides combined Dose escalation will be stopped and only lower doses will be administered subsequently if either of the following occurs after study drug administration one subject experiences clinically significant motor block persisting more than 7 days or four consecutive subjects experience clinically significant motor block persisting more than 5 days
For unsuccessful local anesthetic deposition defined as local anesthetic that could not be deposited immediately adjacent to the femoral nerve as viewed by real-time ultrasound or subject withdrawal from the study the subjects data will not be included in the analysis and the subject dropped from the study subjects will always receive compensation for at least one night in the CTRI--400-even if they are discharged the day of block placement due to failed deposition Remaining subjects will remain within the CTRI and within their bed until discharged home Discharge will occur when quadriceps strength has returned to at least 80 of its baseline value We consider a difference of less than 20 percentage points to be clinically relevant because a 10 side-to-side strength difference is common yet functionally unnoticeable in healthy individuals45 Discharge will occur-at the very earliest-24 hours following initial block placement Therefore the amount of time subjects will spend in the CTRI will depend upon the duration of local anesthetic action which will be variable among subjects and is currently unpredictable without a dose-response curve for peripheral nerve blocks using SKY0402 We anticipate the duration of study participation for each subject to be approximately 72 hours Subjects may withdraw from participation at any time and will receive compensation for the time they have participated up until withdrawal subjects who withdraw the day of block placement will receive 400 However if the research coordinator who is responsible for distributing the compensation is not available at the time of study withdrawal then the subject will need to return to the CTRI the following day or following Monday if withdrawal occurs over the weekend for compensation
Outcome Measurements We have selected measures that have established reliability and validity Staff blinded to treatment group assignment will perform all measures and assessments For all measurements the dominant side will always be tested first followed by the contralateral side Measurements will be performed prior to local anesthetic administration initiation baseline Hour 0 as well as specific post-block time points
Hour Prior to Hour 0 0 010 020 030 040 050
1 115 130 145 2 230 3 330 4 5 6 7 8 9 10 24 Day 2 27-36 48 Day 3 51-60 72 Day 4 75-84 96 Day 5 99-108 120 Day 6
Primary Outcome Measurement
Quadriceps femoris muscle strength Evaluated using a portable isometric force dynamometer to measure the maximum voluntary isometric contraction MVIC in a seated position with the knee flexed at 90ยบ This variable will be presented and analyzed as post pre x 100 For all measurements subjects will be asked to take 2 sec to come to maximum effort contracting the target muscles maintain this effort for 5 sec and then relax
Secondary Outcome Measurement
Sensory level Evaluated using transcutaneous electrical stimulation TES in the same manner as described throughout the anesthesia literature this is a gold standard for regional anesthesia studies After clipping any hair EKG pads will be positioned 2 cm medial to the proximal patella and quadriceps tendon and attached to a nerve stimulator The current will be increased from 0 mA until the subject identifies slight discomfort at which time the current is recorded as the TES value and the nerve stimulator turned off The secondary end point will be the post-administration maximum current absolute values in mA
Safety Assessments Safety assessments will include monitoring of AEs SAEs and vital signs heart rate respiratory rate and blood pressure
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None