A Phase 3 Study of F14 for Management of Pain Following Total Knee Replacement

Study Overview
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Brief Summary
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This is a Phase 3, randomized, double blind, multicenter study to evaluate the analgesic efficacy and safety of a single intra-articular dose of F14 (625 mg sustained release celecoxib) administered concurrent with multimodal analgesia in patients undergoing total knee replacement surgery, compared to multimodal analgesia alone.

Official Title
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A Phase 3, Multicenter, Randomized, Double-Blind, Parallel Group Study of the Efficacy and Safety of a Single Administration of F14 for Postoperative Analgesia in Patients Undergoing Unilateral Total Knee Replacement

Conditions
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Post Operative Pain

Intervention / Treatment
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* Drug: F14
* Drug: 0.25 % Bupivacaine HCl
* Drug: Acetaminophen
* Drug: Methocarbamol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and/or females indicated for primary, unilateral total knee replacement (TKR) Between 45-80 years of age inclusive at the time of signing the informed consent Capable of giving signed informed consent and complying with requirements and restrictions listed in the informed consent form (ICF) and in this protocol Body Mass Index (BMI) ≤ 40 kg/m2 Medically stable as determined by the Investigator, based on physical examination, clinical laboratory tests, and 12-lead electrocardiogram (ECG) findings, as well as medical history from patient and pre-study source documents from other care providers Absence of moderate to severe fixed flexion deformity Absence of moderate to severe varus or valgus deformity Minimum pre-operative flexion arc of 100 degrees Absence of steroid, hyaluronic acid, platelet rich plasma, or any other type of therapeutic injection(s) in the index knee within 3 months before scheduled surgery American Society of Anesthesiologists Physical Status Classification System (ASA-PSC) score ≤ 3 Females of childbearing potential with a negative serum pregnancy test at screening, or males that have a partner who is a woman of child-bearing potential (WOCBP), who agree to employ adequate birth control measures for the full duration of the study. Exclusion Criteria: Known allergy or hypersensitivity to active ingredient celecoxib, OR known allergy or hypersensitivity to sulfonamide antibiotics or sulfa containing drugs when an allergy to celecoxib is unknown Unwilling or unable to discontinue use of nonsteroidal anti-inflammatory drugs (NSAIDs) at least 7 days before study surgery and for 6 weeks following study surgery Unwilling or unable to discontinue use of medical or recreational marijuana or cannabidiol (CBD) at least 10 days before study surgery and for 3 months following study surgery Unwilling or unable to discontinue use of pregabalin, gabapentin or other drugs for neuropathic pain at least 7 days prior to study surgery and for 3 months following study surgery Unwilling or unable to discontinue opioid analgesics at least 7 days prior to surgery Has an allergy or contraindication to opioids or NSAIDs or acetaminophen Active or past infection in the index knee Total or partial knee arthroplasty in the contralateral knee < 6 months prior to study surgery Knee surgery (including cruciate ligament, cartilage or osteotomy) other than simple arthroscopy in either knee in the last 12 months (excluding contralateral total or partial knee replacement) Documented osteonecrosis within previous 12 months Prior or current presence of hardware in index knee other than screws from previous ligament repair that do not require manipulation or removal for TKR surgery Other planned major surgery within 12 months of study surgery Concurrent painful physical condition that is unrelated to the study knee (e.g., back, shoulder or contralateral knee pain) that will require analgesic treatment, such as NSAIDs or opioids, during study follow-up Current NRS pain intensity in the contralateral knee with a severity ≥ 4 Current or historical evidence of any clinically significant disease or condition, especially cardiovascular, pulmonary or neurological, that, in the opinion of the Investigator, may increase the risk of surgery or complicate or affect the subject's study follow-up Suspected opioid abuse in the last 12 months with a score exceeding 5 on the DAST-10 questionnaire, and/or taking opioids ≥ 46 of the previous 90 days, and currently taking >90 mg in morphine milligram equivalents (MME) at least 5 days per week in the month prior to screening. History of alcohol abuse within previous 12 months (score of 4 on CAGE questionnaire) Anxiety Sensitivity Index (ASI) score >40 Fear of Pain Score (FPQ-III) score >120 Uncontrolled depression, mood or anxiety disorder (score exceeding 14 on PHQ-9 questionnaire) Participation or scheduled participation in another clinical study involving an investigational drug or device within one calendar month before screening or during study follow-up Current medical diagnosis or patient-reported seizure disorder Current peripheral neuropathy History of complex regional pain syndrome (CRPS) Diagnosis of clinically significant liver and/or renal abnormalities within previous 2 years Diagnosis of diabetes with HbA1c ≥7 Current inflammatory arthritides (e.g., rheumatoid arthritis, lupus erythematosus, ankylosing spondylitis, psoriatic arthritis), or traumatic bone injuries within 12 months before scheduled surgery, except for clinically stable/non-active gout that does not affect the knee and does not interfere with walking Treatment with immunosuppressants within one calendar month of intervention. Also, antipsychotics, anticholinergics, or anticonvulsants within one calendar month of intervention unless stable dosage established for > one calendar month and does not plan to change during 3 month follow up Diagnosis of skin disorders including psoriasis, vascular insufficiency ulcers, and chronic venous stasis Subjects with sleep apnea associated with a history of postoperative delirium. If symptomatic sleep apnea is currently treated with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP), use must be continued post-operatively History of coronary or vascular stent placed within 3 months Had a malignancy in the last 12 months, except for non-metastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix Positive urine drug screen for disallowed medication pre-operatively on day of study surgery Participation in active or pending personal injury or workers' compensation litigation related to index knee Any reason based on investigator clinical judgment, that subject may be non-compliant with respect to study obligations or assessments

Ages Eligible for Study
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Minimum Age: 45 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: F14 + Multimodal Analgesia<br> | Drug: F14<br>* 625 mg intra-articular sustained-release celecoxib<br>Drug: 0.25 % Bupivacaine HCl<br>* Local anesthetic<br>Drug: Acetaminophen<br>* Analgesic<br>Drug: Methocarbamol<br>* Muscle relaxant<br>|
| Active Comparator: Multimodal Analgesia<br> | Drug: 0.25 % Bupivacaine HCl<br>* Local anesthetic<br>Drug: Acetaminophen<br>* Analgesic<br>Drug: Methocarbamol<br>* Muscle relaxant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-weighted Area Under the Curve (AUC) of numeric rating scale (NRS) pain scores |  | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Index knee range of motion (ROM) at 6 weeks |  | 6 weeks | 
| Time-weighted AUC of NRS pain scores |  | 7 Days | 
| Time-weighted AUC of NRS pain scores |  | 6 weeks | 
| Proportion of subjects using opioid rescue medication at 2 weeks |  | 2 weeks | 
| Time-weighted AUC of NRS pain scores |  | 3 days |