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 study are to evaluate the safety and analgesic efficacy of a single preoperative intrathecal administration of AYX1 Injection at two dose/volume levels.

Official Title
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A Phase 2 Study to Evaluate the Safety & Efficacy of Two Dose/Volume Levels of a Single Intrathecal Preoperative Administration of AYX1 Injection in Patients Undergoing Unilateral Total Knee Arthroplasty

Conditions
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Postsurgical Pain

Intervention / Treatment
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* Drug: AYX1 Injection 660 mg / 6 mL
* Drug: AYX1 Injection 1100 mg / 10 mL
* Drug: Placebo Injection 6 mL
* Drug: Placebo Injection 10 mL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled to undergo primary unilateral TKA for painful osteoarthritis without congenital knee pathology 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 laboratory tests, and 12-lead electrocardiogram (ECG) findings Body Mass Index of 18-40 kg/m2 Stable medical regimen for at least 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 (e.g., rheumatoid arthritis, lupus, ankylosing spondylitis, psoriatic arthritis), with the exception of clinically stable/non-active gout that does not affect the knee and does not interfere with walking Operative arthroscopy in the surgical knee in the last 4 months (except for meniscal repair which will be no shorter than 6 months before randomization) or in the contralateral knee in the last 2 months (or 3 months for meniscal repair), 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 anesthesia using potent inhalational agents, peripheral nerve block (i.e., femoral nerve block), neuroaxial (intrathecal or epidural) opioids postoperatively, or knee capsule injections Received aspirin or any nonsteroidal anti-inflammatory drug (NSAID) prior to randomization within the washout period required by the surgical team for surgery with spinal anesthetic, 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 (e.g., gabapentin, pregabalin) within 2 weeks 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-operatively through Day 28 Treatment with immunosuppressives, antipsychotics, anticholinergics, or anticonvulsants within 1 month of randomization, with the exception of aspirin for cardiac prophylaxis (as long as discontinued within 1 week of randomization) Current neurologic disorder, which could confound the assessment of pain (e.g., 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 Severe pulmonary disease; if symptomatic sleep apnea is currently treated with continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BIPAP), use must be continued postoperatively at least during the inpatient period. Patients with sleep apnea associated with a history of postoperative delirium are excluded. Current evidence of alcohol abuse or history of alcohol-related complications within 1 year of randomization including, but not limited to, alcoholic withdrawal seizures, hallucinations, delirium tremens or detoxification treatment 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 Previous participation in any study involving AYX1 Injection

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 |
| --- | --- |
| Experimental: AYX1 Injection 660 mg / 6 mL<br>Single Intrathecal (spinal) administration of AYX1 Injection (660 mg in 6 mL) just prior to intrathecal administration of spinal anesthetic for knee surgery | Drug: AYX1 Injection 660 mg / 6 mL<br>* 6 mL solution for intrathecal injection with 660 mg of AYX1<br>|
| Placebo Comparator: Placebo Injection 6 mL<br>Single Intrathecal (spinal) administration of Placebo Injection (6 mL) just prior to intrathecal administration of spinal anesthetic for knee surgery | Drug: Placebo Injection 6 mL<br>* 6 mL solution for intrathecal injection; Vehicle formulation designed to mimic AYX1 Injection (with no active drug)<br>|
| Experimental: AYX1 Injection 1100 mg / 10 mL<br>Single Intrathecal (spinal) administration of AYX1 Injection (1100 mg in 10 mL) just prior to intrathecal administration of spinal anesthetic for knee surgery | Drug: AYX1 Injection 1100 mg / 10 mL<br>* 10 mL solution for intrathecal injection with 1100 mg of AYX1<br>|
| Placebo Comparator: Placebo Injection 10 mL<br>Single Intrathecal (spinal) administration of Placebo Injection (10 mL) just prior to intrathecal administration of spinal anesthetic for knee surgery | Drug: Placebo Injection 10 mL<br>* 10 mL solution for intrathecal injection; Vehicle formulation designed to mimic AYX1 Injection (with no active drug)<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 the 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 the outpatient period up to Day 28 | Hospital Discharge to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain with 45 degrees of knee flexion | Mean pain rating on the Numerical Rating Scale (NRS) for 45 degrees passive knee flexion during the inpatient stay | 0-48 hours after surgery | 
| Pain with 90 degrees of knee flexion | Mean pain rating on the Numerical Rating Scale (NRS) for 90 degrees passive knee flexion during the outpatient period to Day 28 | Hospital discharge to Day 28 | 
| 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 |  | Hospital Discharge to Day 28 | 

 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