Knee Osteoarthritis
Conditions
Keywords
SM04690, Wnt pathway inhibitor, osteoarthritis, Samumed, lorecivivint
Brief summary
This phase 3 study is a multicenter, randomized, double-blind, placebo-controlled study of lorecivivint injected intra-articularly (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 radiographs and patient reported outcomes (PROs) to evaluate the safety and efficacy of lorecivivint.
Detailed description
SM04690-OA-11 was a phase 3, 56-week multicenter, randomized, double-blind, placebo-controlled, parallel group study investigating the safety, tolerability and efficacy of LOR 0.07 mg (compared with PBO) injected into the target knee joint of moderately to severely symptomatic knee OA subjects. Patient-reported outcomes included Pain Numeric Rating Scale (NRS) \[0-10\], Western Ontario and McMaster Universities Arthritis Index (WOMAC), and Patient Global Assessment (PGA) of knee osteoarthritis. Joint space as measured by a positioner-assisted posterior-anterior x-ray was the radiographic outcome. The primary efficacy endpoint was change from baseline in target knee Pain NRS at Week 12. Secondary endpoints included change at Week 12 in WOMAC Function and PGA, as well as change in joint space at Week 52.
Interventions
DRUGPlacebo
Healthcare professional-administered intra-articular injection; performed on Day 1
DRUGLorecivivint
Healthcare professional-administered intra-articular injection; performed on Day 1
Sponsors
Biosplice Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Males and females between 40 and 80 years of age, inclusive, in general good health apart from their knee OA 2. Ambulatory (single assistive devices such as canes allowed if needed less than 50% of the time, subjects requiring a walker are excluded) 3. 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) 4. mJSW by radiograph between 1.5 and 4 mm, inclusive, in the target knee within 12 weeks of the Screening Visit as assessed by independent central readers 5. Radiographic disease Stage 2 or 3 in the target knee within 12 weeks of the Screening Visit according to the Kellgren-Lawrence (KL) grading of knee OA as assessed by independent central readers 6. Pain compatible with OA of the knee(s) for at least 26 weeks prior to the Screening Visit 7. Primary source of pain throughout the body is due to OA in the target knee 8. Body mass index (BMI) ≤ 40 kg/m2 at the Screening Visit 9. Widespread Pain Index (WPI) score of ≤ 4 and a Symptom Severity Question 2 (SSQ2) score of ≤ 2 at the Screening Visit and Day 1 10. Pain NRS scores recorded for the target knee on at least 4 out of the 7 days immediately preceding Day 1 11. Pain NRS scores recorded for the nontarget knee on at least 4 out of the 7 days immediately preceding Day 1 12. 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 13. Daily OA knee pain diary average NRS intensity score \< 4 in the nontarget knee on the 11-point (0-10) NRS scale for the 7 days immediately preceding Day 1 14. WOMAC Pain of 20-40 (out of 50) 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) 15. WOMAC Function 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) 16. Willingness to use an electronic diary daily in the evening for the screening period and 56-week study duration 17. 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 18. Subjects with depression or anxiety must be clinically stable for at least 12 weeks prior to the Screening Visit and, if on treatment for depression or anxiety, be on at least 12 weeks of stable therapy 19. Full understanding of the requirements of the study and willingness to comply with all study visits and assessments 20. 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
Exclusion criteria
1. Pregnant women, breastfeeding woman, 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 2. Women who are not post-menopausal or permanently surgically sterile who are sexually active, and who are not willing to use birth control during the study period 3. Men who are sexually active and of reproductive potential, who have partners who are capable of becoming pregnant, and who are not willing to use birth control during the study period 4. Significant malalignment of anatomical axis (medial angle formed by the femur and tibia) of the target knee (varus \> 10°, valgus \> 10°) by radiograph within 12 weeks of the Screening Visit as assessed by independent central readers 5. Partial or complete joint replacement in either knee 6. Currently requires use of a lower extremity prosthesis, and/or a structural knee brace (i.e., a knee brace that contains hardware) 7. Any surgery (e.g., arthroscopy) in either knee within 26 weeks prior to Day 1 8. 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 9. Effusion of the target knee clinically requiring aspiration within 12 weeks prior to Day 1 10. Use of electrotherapy, acupuncture, physical therapy, therapeutic ultrasound, and/or chiropractic treatments for knee OA within 4 weeks prior to Day 1 11. Any bone fracture(s) within 26 weeks prior to the Screening Visit 12. Previous treatment with SM04690 13. Subjects who have previously failed screening on this protocol and fail to meet rescreening criteria 14. 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 the Screening Visit, or planned participation in any such trial 15. Treatment with systemic (oral, intramuscular, or intravenous) glucocorticoids ≥10 mg prednisone or the equivalent per day within 4 weeks prior to Day 1, or subjects on \<10 mg prednisone or the equivalent per day who have not maintained a stable regimen for at least 2 weeks prior to Day 1 in the opinion of the Investigator 16. Use of centrally acting analgesics within 12 weeks prior to Day 1 17. Use of anticonvulsants within 12 weeks prior to Day 1 18. Subjects requiring the use of opioids \> 1x per week within 12 weeks prior to Day 1 19. Topical local anesthetic agents (gels, creams, or patches such as the Lidoderm patch) used for the treatment of knee OA within 7 days of Day 1 20. Planned surgery scheduled during the study period, not including non-surgical invasive procedures conducted for a diagnostic or therapeutic purpose scheduled during the study period 21. 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 22. Clinically significant abnormal screening hematology values, blood chemistry values, or urinalysis values as determined by the Investigator 23. Any condition, 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 24. 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 25. 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 26. History of mania, bipolar disorder, psychotic disorder, schizophrenia, or schizoaffective disorder 27. 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 28. 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. 29. Hemoglobin A1c (HbA1c) \>9 at the Screening Visit 30. If using NSAIDs and/or acetaminophen, subjects who have not maintained a stable regimen in the opinion of the Investigator for at least 4 weeks prior to Day 1 31. Any contraindications for an IA injection in the target knee in the opinion of the Investigator 32. Subjects who have a current or pending disability claim, workers' compensation, or litigation(s) that may compromise response to treatment 33. 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 34. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in OA Pain in the Target Knee (Pain NRS) | Baseline and Week 12 | Evaluate change from baseline OA pain in the target knee as assessed by the weekly averages of 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in OA Pain in the Target Knee (Pain NRS) | Baseline and Week 24 | Evaluate change from baseline OA pain in the target knee as assessed by the weekly averages of 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. |
| Change From Baseline in OA Function in the Target Knee (WOMAC Function) | Baseline and Week 12 | Evaluate 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). 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 an 11-point numeric rating scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Function raw subscore ranges from 0 to 170, and is scaled 0 (highest overall function) to 100 (lowest overall function) for analysis and reporting. |
| Change From Baseline in OA Disease Activity (Patient Global Assessment) | Baseline and Week 12 | Evaluate change from baseline OA disease activity as assessed by 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). For analysis, Patient Global Assessment scores were scaled to \[0-100\], where 0 represents "Very Good" and 100 represents "Very Bad". |
Countries
United States
Contacts
STUDY_DIRECTORYusuf Yazici, M.D.
Biosplice Therapeutics, Inc.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61.0 years STANDARD_DEVIATION 8.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 100 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 199 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Kellgren-Lawrence Grade Grade 2 | 124 Participants |
| Kellgren-Lawrence Grade Grade 3 | 124 Participants |
| Medial Joint Space Width | 2.61 mm STANDARD_DEVIATION 0.74 |
| Osteoarthritis Symptoms Laterality Bilateral | 339 Participants |
| Osteoarthritis Symptoms Laterality Unilateral | 80 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 13 Participants |
| Race (NIH/OMB) Black or African American | 66 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 171 Participants |
| Sex: Female, Male Female | 165 Participants |
| Sex: Female, Male Male | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 249 | 0 / 252 |
| other Total, other adverse events | 85 / 249 | 81 / 252 |
| serious Total, serious adverse events | 12 / 249 | 13 / 252 |
Outcome results
None listed