Bunionectomy, Hallux Valgus
Conditions
Keywords
ALX006, Bupivacaine, Popliteal fossa nerve block, Analgesia, Post-operative analgesia
Brief summary
This is a Phase 2, randomized, double-blind, active-controlled, dose-escalation study evaluating the safety, pharmacokinetics, efficacy, and pharmacodynamics of ALX006, an extended-release bupivacaine formulation, administered as a single-dose sciatic nerve block in the popliteal fossa in adult subjects undergoing primary unilateral bunionectomy. Approximately 60 subjects will be enrolled across 3 sequential dose cohorts (100 mg, 150 mg, 200 mg ALX006), with each cohort comparing ALX006 against MARCAINE 0.25% (bupivacaine HCl 50 mg) as the active comparator at a 3:1 randomization ratio. Dose escalation between cohorts is governed by an Independent Data Monitoring Committee.
Interventions
DRUGALX006 (bupivacaine extended-release injection)
ALX006 (50 mg/mL bupivacaine free base)
Bupivacaine HCl 0.25% plain (2.5 mg/mL)
PROCEDURESciatic Nerve Block
Sciatic nerve block in the popliteal fossa
Sponsors
Rebel Medicine Inc
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
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
* Male or female, ages 18 or older at screening * American Society of Anesthesiologists (ASA) physical status 1, 2, or 3 (see Appendix 5) * Able to provide informed consent, adhere to the study schedule, and complete all study assessments * Primary surgical indication is related to a bunion deformity (i.e., hallux valgus) and subject is scheduled to undergo a primary unilateral distal metaphyseal osteotomy procedure (i.e., Austin procedure) * Indicated to undergo elective (i.e., not emergency) bunionectomy * Body Mass Index (BMI) ≥18 and \<40 kg/m2
Exclusion criteria
* Allergy, hypersensitivity, intolerance, or contraindication to any of the study medications for which an alternative is not named in the protocol (e.g., amide-type local anesthetics, opioids, bupivacaine HCl, NSAIDs) * Concurrent painful physical condition (e.g. arthritis, fibromyalgia, cancer) that may require analgesic treatment with NSAIDs or opioids in the post dosing period for pain that is not strictly related to the surgery and which, in the Investigator's opinion, may confound the post dosing assessments * Inadequate sensory function of the foot/ankle as assessed by the Investigator * History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within the past two (2) years * Administration of an investigational drug within thirty (30) days or five (5) elimination half-lives of such investigational drug, whichever is longer, prior to study drug administration, or planned administration of another investigational product or procedure during the subject's participation in this study * Administration of any local anesthetic within 72 hours prior to administration of study drug, other than for pretreatment prior to a needle placement * Require additional local anesthetic other than study drug or lidocaine used for the Mayo field block or for pretreatment prior to a needle placement during the study period * Uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the Investigator, could interfere with study assessments or compliance * Currently pregnant, nursing, or planning to become pregnant during the study * Clinically significant medical disease that, in the opinion of the Investigator would make participation in a clinical study inappropriate. This includes diabetic neuropathy, coagulation or bleeding disorders, severe peripheral vascular disease, renal insufficiency, hepatic dysfunction, glucose-6-phosphate dehydrogenase deficiency or other conditions that would constitute a contraindication to participation in the study * Confirmed clinically significant vital sign or ECG abnormality, including QTcF \> 450 msec at Screening * Has any of the following laboratory abnormalities during Screening (1 retest permitted): 1. History of liver cirrhosis, having an aspartate aminotransferase \>3x the upper limit of normal (ULN), or having an alanine aminotransferase \> 3x ULN. 2. Severe kidney function impairment as defined by estimated glomerular filtration rate (eGFR) by CKD-EPI 2021 equation \<30 mL/min/1.73 m²or on dialysis. 3. Platelet count \< 100,000/uL, hemoglobin \< 12 g/dL, or hematocrit \< 35%. * Currently on a gabapentinoid (e.g., gabapentin, pregabalin \[Lyrica\]) or a serotonin-norepinephrine reuptake inhibitor (SNRI) with recognized analgesic properties (e.g., duloxetine \[Cymbalta\]) that cannot be discontinued within 30 days before surgery. Other agents with documented efficacy in modulating acute or chronic pain may be excluded at the discretion of the Investigator in consultation with the Sponsor Medical Monitor. Selective serotonin reuptake inhibitors (SSRIs) are not excluded under this criterion. * Current use of systemic glucocorticoids within thirty (30) days of randomization in this study * Use of dexmedetomidine HCl or clonidine within three (3) days of study drug administration * Any use of marijuana (including tetrahydrocannabinol (THC) and cannabidiol (CBD)) within thirty (30) days prior to randomization, or planned use during the study. * Chronic opioid use within thirty (30) days prior to randomization (average ≥30 oral morphine mg equivalents/day)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of treatment-emergent adverse events (TEAEs) | From start of nerve block procedure through 360 Hour Visit (Day 15) | TEAEs graded by CTCAE v5.0, summarized by System Organ Class and Preferred Term |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median time to first postsurgical opioid consumption | End of surgery through 168 hours post-surgery | Time from end of surgery to administration of the first postsurgical opioid dose. |
| Plasma bupivacaine maximum observed concentration (Cmax) | Pre-dose through 168 hours post-block administration | Maximum observed plasma bupivacaine concentration following single-dose administration |
| Time to maximum plasma bupivacaine concentration (Tmax) | Pre-dose through 168 hours post-block administration | Time from end of block administration to the maximum observed plasma bupivacaine concentration. |
| Apparent terminal elimination half-life of bupivacaine (t½el) | Pre-dose through 168 hours post-block administration | Apparent terminal elimination half-life of plasma bupivacaine |
| Apparent clearance of bupivacaine (CL/F) | Pre-dose through 168 hours post-block administration | Apparent clearance of bupivacaine following perineural administration, derived by non-compartmental analysis. |
| AUC of NRS pain intensity scores 0-72 hours post-surgery | 0 to 72 hours post-surgery | Area under the curve of 11-point Numeric Rating Scale (0 = no pain; 10 = worst possible pain) for current pain in operative foot |
| AUC of NRS pain intensity scores 0-96 hours post-surgery | 0 to 96 hours post-surgery | Area under the curve of 11-point Numeric Rating Scale (0 = no pain; 10 = worst possible pain) for current pain in operative foot |
| AUC of NRS pain intensity scores 0-120 hours post-surgery | 0 to 120 hours post-surgery | Area under the curve of 11-point Numeric Rating Scale (0 = no pain; 10 = worst possible pain) for current pain in operative foot |
| Total postsurgical opioid consumption in oral morphine equivalents (OMED) from 0 to 72 hours post-surgery | 0 to 72 hours post-surgery | Cumulative opioid consumption from the end of surgery through 72 hours, calculated as oral morphine equivalent dose (OMED) using CDC opioid morphine equivalent conversion factors. |
| Total postsurgical opioid consumption in oral morphine equivalents (OMED) from 0 to 96 hours post-surgery | 0 to 96 hours post-surgery | Cumulative opioid consumption from the end of surgery through 96 hours, calculated as oral morphine equivalent dose (OMED) using CDC opioid morphine equivalent conversion factors. |
| Total postsurgical opioid consumption in oral morphine equivalents (OMED) from 0 to 120 hours post-surgery | 0 to 120 hours post-surgery | Cumulative opioid consumption from the end of surgery through 120 hours, calculated as oral morphine equivalent dose (OMED) using CDC opioid morphine equivalent conversion factors. |
| Percentage of opioid-free subjects through 72 hours post-surgery | 0 to 72 hours post-surgery | Proportion of subjects who consumed no opioid medication from the end of surgery through 72 hours. |
| Percentage of opioid-free subjects through 120 hours post-surgery | 0 to 120 hours post-surgery | Proportion of subjects who consumed no opioid medication from the end of surgery through 120 hours. |
| Percentage of opioid-free subjects through 96 hours post-surgery | 0 to 96 hours post-surgery | Proportion of subjects who consumed no opioid medication from the end of surgery through 96 hours. |
Countries
United States
Contacts
CONTACTCaleb Lade, MD
STUDY_DIRECTORJayant Agarwal, MD
Rebel Medicine Inc
Outcome results
None listed