A Study Utilizing Patient-Reported Outcomes to Evaluate the Safety and Efficacy of Lorecivivint (SM04690) for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis

Study Overview
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Brief Summary
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This phase 3 study is a multicenter, randomized, double-blind, placebo-controlled study of lorecivivint injected intraarticularly (IA) into the target knee (most painful) joint of moderately to severely symptomatic osteoarthritis (OA) subjects at a single dose of 0.07 mg lorecivivint per 2 mL injection. This study will utilize patient reported outcomes (PROs) to evaluate the safety and efficacy of lorecivivint.

Official Title
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A Phase 3, 28-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of a Single Injection of SM04690 Injected in the Target Knee Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects

Conditions
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Knee Osteoarthritis

Intervention / Treatment
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* Drug: Lorecivivint
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Males and females between 40 and 80 years of age, inclusive, in general good health apart from their knee OA Ambulatory (single assistive devices such as canes allowed if needed less than 50% of the time, subjects requiring a walker are excluded) Diagnosis of femorotibial OA in the target knee by standard American College of Rheumatology (ACR) criteria at the Screening Visit (clinical AND radiographic criteria); OA of the knee is not to be secondary to any rheumatologic conditions (e.g., rheumatoid arthritis) Radiographic disease Stage 2 or 3 in target knee within 24 weeks of the Screening Visit according to the Kellgren-Lawrence (KL) grading of knee OA as assessed by independent central readers Qualifying mean score on the 24-h average pain score (0-10 numeric rating scale) Pain compatible with OA of the knee(s) for at least 26 weeks prior to the Screening Visit Primary source of pain throughout the body is due to OA in the target knee Body mass index (BMI) ≤ 35 kg/m2 at the Screening Visit Negative drug test for amphetamine, buprenorphine, cocaine, methadone, opiates, phencyclidine (PCP), propoxyphene, barbiturates, benzodiazepine, methaqualone, and tricyclic antidepressants, unless any of these drugs are allowed per protocol and prescribed by a physician to treat a specific condition Key Exclusion Criteria: Pregnant women, breastfeeding women, and women who are not post-menopausal (defined as 12 months with no menses without an alternative medical cause) or permanently surgically sterile (includes hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) who have a positive or indeterminate pregnancy test result at the Screening Visit or Day 1 Significant malalignment of anatomical axis (medial angle formed by the femur and tibia) of the target knee (varus > 10°, valgus > 10°) by radiograph within 24 weeks of the Screening Visit as assessed by independent central readers Partial or complete joint replacement in either knee Currently requires use of a lower extremity prosthesis, and/or a structural knee brace (i.e., a knee brace that contains hardware) Any surgery (e.g., arthroscopy) in either knee within 26 weeks prior to Day 1 Intra-articular (IA) injection into the target knee with a therapeutic aim including, but not limited to hyaluronic acid, platelet-rich plasma (PRP), and stem cell therapies within 26 weeks prior to Day 1; or IA glucocorticoids within 12 weeks prior to Day 1 allowed Previous treatment with lorecivivint (SM04690) Subjects who have previously failed screening on this protocol and fail to meet re-screening criteria Participation in a clinical research trial that included the receipt of an investigational product or any experimental therapeutic procedure within 26 weeks prior to the Screening Visit, or planned participation in any such trial Subjects requiring the use of opioids > 1x per week within 12 weeks prior to Day 1 History of malignancy within the last 5 years; not including subjects with prior history of adequately treated in situ cervical cancer or basal or squamous cell skin cancer Clinically significant abnormal screening hematology values, blood chemistry values, or urinalysis values as determined by the Investigator Any known active infections, including urinary tract infection, upper respiratory tract infection, sinusitis, suspicion of IA infection, hepatitis B or hepatitis C infection, and/or infections that may compromise the immune system such as human immunodeficiency virus (HIV) at Day 1

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: Lorecivivint<br>Healthcare professional-administered intra-articular injection; performed on Day 1. | Drug: Lorecivivint<br>* One intra-articular injection of 0.07 mg lorecivivint in 2 m vehicle<br>* Other names: SM04690;|
| Placebo Comparator: Vehicle<br>Healthcare professional-administered intra-articular injection; performed on Day 1. | Drug: Placebo<br>* One intra-articular injection of 0 mg lorecivivint in 2 m vehicle<br>* Other names: Vehicle;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline OA pain in the target knee as assessed by the weekly average of daily pain numeric rating scale (NRS) at Week 12 | Evaluate change from baseline OA pain in the target knee as assessed by the weekly average of daily pain NRS at Week 12. The pain NRS is an 11-point scale [0-10] for subject self-reporting of average knee pain in the last 24 hours; 0 indicates no pain, and 10 represents the worst possible pain. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline OA pain in the target knee as assessed by the weekly average of daily pain numeric rating scale (NRS) at Week 24 | Evaluate change from baseline OA pain in the target knee as assessed by the weekly average of daily pain NRS at Week 24. The pain NRS is an 11-point scale [0-10] for subject self-reporting of average knee pain in the last 24 hours; 0 indicates no pain, and 10 represents the worst possible pain. | Baseline and Week 24 | 
| Change from baseline OA function in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function subscore (WOMAC Function) at Weeks 12 and 24 | Evaluate change from baseline OA function in the target knee as assessed by WOMAC Function subscore at Weeks 12 and 24. The WOMAC is a widely-used, proprietary outcome measurement tool used to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 4 (highest pain/highest stiffness/lowest function). The WOMAC Function subscore ranges from 0 to 68. | Baseline, Weeks 12 and 24 | 
| Change from baseline OA disease activity as assessed by Patient Global Assessment at Weeks 12 and 24 | Evaluate change from baseline OA disease activity as assessed by Patient Global Assessment at Weeks 12 and 24. The Patient Global Assessment is an 11-point [0-10] Numeric Rating Scale [NRS] on which the subjects will rate how they feel their target knee OA is doing, considering all the ways in which their target knee OA may affect them. The NRS is anchored by descriptors at each end (Very Good on the left and Very Bad on the right). | Baseline, Weeks 12 and 24 | 
| Change from baseline in usage of nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen for target knee OA pain at Week 24 | Evaluate change from baseline in usage of NSAIDs and acetaminophen for target knee OA pain at Week 24. | Baseline, Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SM04690, Wnt pathway inhibitor, osteoarthritis, Samumed, lorecivivint