A Study Evaluating the Safety, Tolerability and Efficacy of Two Injections of SM04690 for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis

Study Overview
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Brief Summary
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The primary purpose of this phase 2, placebo-controlled, double-blind, parallel group study is to provide an initial evaluation of two intra-articular (IA) injections of SM04690 (each at the dose of 0.07mg per 2mL injection) approximately six months apart into the target knee of moderately to severely symptomatic osteoarthritis (OA) subjects. Subjects who complete this 52-week long study will be eligible to enter the extension phase for an additional 52 weeks of treatment.

Official Title
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A Phase 2, 52-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of Two Injections 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: Placebo
* Drug: SM04690


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females between 40 and 80 years of age, inclusive, in general good health Ambulatory Diagnosis of femorotibial OA in the target knee by standard American College of Rheumatology (ACR) criteria at Screening Visit 1 (clinical AND radiographic criteria); OA of the knee is not to be secondary to any rheumatologic conditions (e.g., rheumatoid arthritis) Pain compatible with OA of the knee(s) for at least 26 weeks prior to Screening Visit 1 Primary source of pain throughout the body is due to OA in the target knee Daily OA knee pain diary average NRS intensity score ≥ 4 and ≤ 8 in the target knee on the 11-point (0-10) NRS scale for the 7 days immediately preceding Day 1 Pain NRS scores recorded for the target knee on at least 4 out of the 7 days immediately preceding Day 1 Daily OA knee pain diary average NRS intensity score < 4 in the non-target knee on the 11-point (0-10) NRS scale for the 7 days immediately preceding Day 1 Pain NRS scores recorded for the non-target knee on at least 4 out of the 7 days immediately preceding Day 1 WOMAC pain subscore of 20-40 (out of 50) and WOMAC physical function subscore of 68-136 (out of 170) for the target knee at baseline, regardless of if the subject is on symptomatic oral treatment (baseline questionnaire completed during the screening period prior to randomization) Widespread Pain Index (WPI) score of ≤ 4 and a Symptom Severity Question 2 (SSQ2) score of ≤ 2 at Screening Visit 1 Willingness to use an electronic diary on a daily basis in the evening for the screening period and 104-week study duration Negative drug test for amphetamine, buprenorphine, cocaine, methadone, opiates, phencyclidine (PCP), propoxyphene, barbiturates, benzodiazepine, methaqualone, and tricyclic antidepressants, except if any such drugs are clinically indicated and allowed by the protocol, at Screening Visit 1. Subjects with depression or anxiety must be clinically stable for 12 weeks prior to Screening Visit 1 in the opinion of the Investigator and, if on treatment for depression or anxiety, be on 12 weeks of stable therapy Full understanding of the requirements of the study and willingness to comply with all study visits and assessments Subjects must have read and understood the Informed Consent Form (ICF), and must have signed and dated it prior to any study-related procedure being performed Subject's Screening Visit 1 visit must occur while enrollment into the study is open Subject is able to have a Screening Visit 2 qCT image acquired that does not require a re-scan as determined by the central imaging vendor Exclusion Criteria: Pregnant and 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) and have a positive or indeterminate pregnancy result at Screening Visit 2 or Day 1 Women who are not post-menopausal or permanently surgically sterile, who are sexually active, and who are not willing to use birth control (as outlined in Section 5.3.1) during the study period Males who are sexually active and have a partner who is capable of becoming pregnant, neither of whom have had surgery to become sterilized or who are not using birth control as outlined in Section 5.3.1 Body mass index (BMI) > 35 Partial or complete joint replacement in either knee Currently requires: regular use (in the opinion of the Investigator) of ambulatory assistive devices (e.g., wheelchair, parallel bars, walker, canes, or crutches), or use of a lower extremity prosthesis, and/or a structural knee brace (i.e., a knee brace that contains hardware) Radiographic disease Stage 0, 1, or 4 in the target knee at Screening Visit 1 according to the Kellgren-Lawrence grading of knee OA as assessed by independent central readers Previous enrollment in a Samumed clinical trial investigating SM04690 Any surgery (e.g., arthroscopy) in either knee within 26 weeks prior to Screening Visit 1 Any bone fracture(s) within 26 weeks prior to Screening Visit 1 Any surgery scheduled during the study period. Non-surgical invasive procedures conducted for a diagnostic or therapeutic purpose scheduled during the study period are not prohibited.(refer to section 7.6) Significant and clinically evident misalignment of either knee that would impact subject function, as determined by the Investigator History of malignancy within the last 5 years; however, subjects with prior history of in situ basal or squamous cell skin cancer are eligible if completely excised. Subjects with other malignancies are eligible if they have been continuously disease free for at least 5 years prior to Screening Visit 1 Clinically significant abnormal screening hematology values, blood chemistry values, or urinalysis values as determined by the Investigator Any condition, including laboratory findings not included in the Screening Visit 2 laboratory tests and findings in the medical history or in the pre-study assessments, that, in the opinion of the Investigator, constitutes a risk or contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation Comorbid conditions that could affect study endpoint assessments of the target knee, including, but not limited to, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, gout or pseudogout, and fibromyalgia Other conditions that, in the opinion of the Investigator, could affect study endpoint assessments of either knee, including, but not limited to, peripheral neuropathy (e.g., diabetic neuropathy), symptomatic hip osteoarthritis, symptomatic degenerative disc disease, and patellofemoral syndrome History of mania, bipolar disorder, psychotic disorder, schizophrenia, schizoaffective disorder, major depressive disorder, or generalized anxiety disorder Participation in a clinical research trial that included the receipt of an investigational product (IP) or any experimental therapeutic procedure within 26 weeks prior to Screening Visit 1, or planned participation in any such trial Treatment of the target knee with intra-articular glucocorticoids (e.g., methylprednisolone) within 12 weeks prior to Screening Visit 1 Any intra-articular injection into the target knee with a therapeutic aim including, but not limited to, viscosupplementation (e.g., hyaluronic acid), platelet-rich plasma (PRP), and stem cell therapies within 24 weeks prior to Screening Visit 1; treatment of the target knee with intra-articular glucocorticoids greater than 12 weeks prior to Screening Visit 1 is allowed Treatment with systemic (oral, intramuscular, or intravenous)glucocorticoids greater than 10 mg prednisone or the equivalent per day within 4 weeks prior to Screening Visit 1 Effusion of the target knee clinically requiring aspiration within 12 weeks prior to Screening Visit 1 Use of electrotherapy, acupuncture, and/or chiropractic treatments for knee OA within 4 weeks prior to Screening Visit 1 (refer to Appendix 1) Any known active infections, including urinary tract infection, upper respiratory tract infection, sinusitis, suspicion of intra-articular 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 Subjects requiring the chronic use (i.e., regular and consistent use for ≥ 12 weeks) of centrally acting analgesics (e.g., duloxetine) (refer to Appendix 1) within 12 weeks prior to Screening Visit 1 Subjects requiring the chronic use (i.e., regular and consistent use for ≥ 12 weeks) of anticonvulsants (not listed in Appendix 1 ) within 12 weeks prior to Screening Visit 1, unless used for seizure or migraine prophylaxis Subjects requiring the usage of opioids >1x per week within 12 weeks prior to Screening Visit 1 Topical local anesthetic agents (gels, creams, or patches such as the Lidoderm patch) used for the treatment of knee OA within 7 days of Screening Visit 1 Any chronic condition that has not been well controlled or subjects with a chronic condition who have not maintained a stable therapeutic regimen of a prescription therapy in the opinion of the Investigator. In addition, subjects with an HbA1c >9 at Screening Visit 2 will be excluded. If on NSAIDs for the treatment of OA pain, subjects who have not maintained a stable regimen in the opinion of the Investigator at Screening Visit 1 Any contraindications for performing DXA scans of the hips or spine including but not limited to: other radiological investigations using contrast media or radionuclides within 7 days of Screening Visit 2 weight that precludes scanning at these sites Subjects who have had a single or bilateral hip replacement Subjects who have a current or pending disability claim, workers' compensation, or litigation(s) that may compromise response to treatment Subjects who are immediate family members (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the study at any investigative site, or are directly affiliated with the study at any investigative site Subjects employed by Samumed, LLC, or any of its affiliates or development partners (that is, an employee, temporary contract worker, or designee) responsible for the conduct of the study, or who are immediate family members (spouse, parent, child, or sibling; biological or legally adopted) of said employees responsible for the conduct of the study Subject has non-evaluable DXA scans of the hips or spine (i.e., pins, screws, any surgical implant, fracture, or severe degenerative changes in the region of interest), as assessed by the central imaging vendor at the time of screening

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: 0.07 mg SM04690<br>Intra-articular injections of 0.07 mg SM04690 in 2 mL vehicle | Drug: SM04690<br>* Healthcare professional-administered intra-articular injections; first performed on Day 1 and second at Week 24. (In the extension phase, healthcare professional-administered intra-articular injections; first performed at Week 52 and second at Week 76.)<br>|
| Placebo Comparator: Vehicle<br>Intra-articular injections of 0 mg SM04690 in 2 mL vehicle | Drug: Placebo<br>* Healthcare professional-administered intra-articular injections; first performed on Day 1 and second at Week 24. (In the extension phase, healthcare professional-administered intra-articular injections; first performed at Week 52 and second at Week 76.)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in BMD from baseline in the treated knee compared to placebo by qCT | Evaluate change in bone mineral density (BMD) from baseline in the treated knee compared to placebo by quantitative computed tomography (qCT) | Baseline, and Week 52 | 
| Safety of SM04690 treatment: adverse events (AEs) and serious adverse events (SAEs) | Evaluate the safety of SM04690 treatment by the occurrence of AEs and SAEs. | Baseline through Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline OA pain in the target knee (NRS) | Evaluate change from baseline OA pain in the target knee at each week as assessed by the weekly averages of subject-reported daily pain Numeric Rating Scale (NRS). 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 through Week 52 | 
| Change from baseline OA pain in the target knee (WOMAC pain subscore) | Evaluate change from baseline OA pain in the target knee as assessed by subject-reported monthly Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore. 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 Pain subscore ranges from 0 to 20. | Baseline through Week 52 | 
| Change from baseline OA function in the target knee (WOMAC physical function subscore) | Evaluate change from baseline OA function in the target knee as assessed by subject-reported monthly WOMAC physical function subscore (WOMAC Function). 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 through Week 52 | 
| Change from baseline OA disease activity | Evaluate change from baseline OA disease activity as assessed by subject-reported monthly Patient Global Assessment. 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 through Week 52 | 
| Change from baseline in medial joint space width (mJSW) of the target knee | Evaluate change from baseline in medial joint space width (mJSW) as documented by radiograph of the target knee. | Baseline, Weeks 24 and 52 | 
| Change in BMD from baseline in the treated knee compared to placebo by qCT | Evaluate change in BMD from baseline in the treated knee compared to placebo by qCT | Baseline and Weeks 12, 24 and 36 | 
| Difference in the change in BMD from baseline between the treated and untreated knee by qCT | Evaluate difference in the change in BMD from baseline between the treated and untreated knee by qCT | Baseline and Weeks 12, 24, 36 and 52 | 
| Change in BMD from baseline by DXA of the spine and hips | Evaluate change in BMD from baseline by dual-energy X-ray absorptiometry (DXA) of the spine and hips | Baseline, and Weeks 24 and 52 | 
| Change in serum bone biomarker PINP from baseline | Evaluate change in serum bone biomarker N-terminal propeptide of procollagen type I [PINP] from baseline | Baseline through Week 52 | 
| Change in serum bone biomarker β-CTX from baseline | Evaluate change in serum bone biomarker β-C-terminal telopeptide [β-CTX] from baseline | Baseline through Week 52 | 
| Change in a serum cartilage biomarker COMP from baseline | Evaluate change in serum cartilage biomarker (e.g., cartilage oligomeric matrix protein [COMP]) from baseline | Baseline through Week 52 | 

 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