Study to Evaluate Safety/Efficacy of a Single Pre-Op Dose of AYX1 Injection to Treat Pain After Knee Replacement Surgery

Study Overview
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Brief Summary
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The objectives of this proof of concept study are to evaluate the safety and preventive analgesic efficacy of a single preoperative intrathecal administration of AYX1 Injection in patients undergoing unilateral total knee arthroplasty.

Official Title
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Study to Evaluate the Safety & Efficacy of a Single Intrathecal Pre-Operative Administration of AYX1 Injection at Two Dose Levels Compared to Placebo in Patients Undergoing Unilateral Total Knee Arthroplasty (TKA)

Conditions
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Postsurgical Pain

Intervention / Treatment
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* Drug: Placebo Injection
* Drug: AYX1 Injection 110 mg
* Drug: AYX1 Injection 330 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled to undergo primary unilateral TKA for painful osteoarthritis American Society of Anesthesiologists Physical Status Classification System ≤ 3 Medically stable as determined by the Investigator based on pre-study medical history, physical/neurological examination, clinical lab tests, and 12-lead ECG findings Body mass index of 18-40 kg/m2 Stable medical regimen for ≥ 1 month before randomization Able to read and understand study instructions in English, and willing and able to comply with all study procedures Exclusion Criteria: More than 2 other current focal areas of pain, none greater in intensity than the target knee and no other active chronic pain conditions that would compromise operative knee pain evaluation Inflammatory arthridities (i.e., rheumatoid arthritis, lupus, ankylosing spondylitis, psoriatic arthritis, gout) Operative arthroscopy in the surgical knee in the last 6 months, or other prior surgery in either knee in the last 12 months, except for diagnostic arthroscopy Planned use of any of the following for TKA: general endotracheal anesthesia (GETA), peripheral nerve block (i.e., femoral nerve block), neuroaxial (intrathecal or epidural) opioids postoperatively, or knee capsule injections Received aspirin within 1 week of randomization, or any nonsteroidal anti-inflammatory drug (NSAID) within 5 half-lives prior to randomization, or planned use of NSAIDS post-operatively through Day 28 Use of more than 20 mg per day (on average) of oral morphine or its equivalent within 1 month prior to randomization Use of adjuvant analgesics for chronic pain control (i.e., gabapentin, pregabalin) during the month prior to randomization or planned use post-operatively through Day 28 Daily use of benzodiazepines in the 3 months prior to randomization (unless used for sleep and dosage will be consistent after surgery) Use of systemic corticosteroids (does not include inhaled steroids) within 3 months or intra-articular steroid injections within 1 month prior to randomization, or planned use of either post-op through Day 28 Treatment with antibiotics or antivirals (EXCEPTION: topical treatments), immunosuppressives, antipsychotics, anticholinergics, or anticonvulsants within 1 month of randomization, with the exception of prescribed pre-surgical prophylactic antibiotics, and aspirin for cardiac prophylaxis (as long as discontinued within 1 week of randomization Current neurologic disorder, which could confound the assessment of pain (i.e., Parkinson's, Multiple Sclerosis) Current active depression symptoms Has had a change in dose or regimen of SSRIs or SNRIs for depression within 1 month of randomization Mini Mental State Exam score < 24 at screening Current history of insulin dependent diabetes mellitus, or autoimmune conditions Severe chronic obstructive or restrictive pulmonary disease, current diagnosis of obstructive sleep apnea documented by a sleep laboratory study, or current home use of continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BIPAP) Current evidence of alcohol abuse or history of alcohol-related complications within 1 year of randomization Known or suspected history of illicit drug abuse within 1 year before randomization, current or planned use of medical marijuana, or history of opioid dependence within 2 years before randomization Any malignancy within the past year, with the exception of basal cell carcinoma or uncomplicated or stable skin cancers documented to not require further or immediate treatment Women who are pregnant or nursing

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (Vehicle) Injection<br>Single Intrathecal (spinal) administration of Placebo Injection just prior to intrathecal administration of spinal anesthetic for knee surgery | Drug: Placebo Injection<br>* 3mL solution for intrathecal injection; Vehicle formulation designed to mimic AYX1 Injection (with no active drug)<br>|
| Experimental: AYX1 Injection 110 mg<br>Single Intrathecal (spinal) administration of AYX1 Injection (110 mg) just prior to intrathecal administration of spinal anesthetic for knee surgery | Drug: AYX1 Injection 110 mg<br>* 3mL solution for intrathecal injection with 110 mg of AYX1<br>|
| Experimental: AYX1 Injection 330 mg<br>Single Intrathecal (spinal) administration of AYX1 Injection (330 mg) just prior to intrathecal administration of spinal anesthetic for knee surgery | Drug: AYX1 Injection 330 mg<br>* 3mL solution for intrathecal injection with 330 mg of AYX1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain with walking during 5 meter walk test | Mean pain rating on the Numerical Rating Scale (NRS) with walking during the 5 meter walk test during inpatient stay 0-48 hours | 0-48 hours after surgery | 
| Pain with walking during 15 meter walk test | Mean pain rating on the Numerical Rating Scale (NRS) with walking during the 15 meter walk test during outpatient period up to Day 28 | From hospital discharge to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total use of opioid medications (morphine equivalents) during hospital stay |  | 0-48 hours after surgery | 
| Total use of opioid medications (morphine equivalents) post-discharge to Day 28 |  | From hospital discharge to Day 28 | 
| Pain with 45 degrees of knee flexion | Mean pain rating on the Numerical Rating Scale (NRS) for 45 degrees active knee flexion | 0-48 hours after surgery | 
| Pain with 90 degrees of knee flexion | Mean pain rating on the Numerical Rating Scale (NRS) for 90 degrees active knee flexion | From 7 to 28 days after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postsurgical pain, Total knee arthroplasty, Total knee replacement