A Study to Evaluate the Safety and Efficacy of Topically Applied TV-45070 (Ointment) in Participants With Primary Osteoarthritis (OA) Affecting a Single Knee

Study Overview
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Brief Summary
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The primary purpose of the study is to evaluate the change from baseline after 4 weeks of topical administration of TV-45070 (4% and 8% ointment) compared with placebo for the relief of symptoms of primary OA affecting a single knee

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Topically Applied TV-45070 (4% and 8% w/w Ointment) in Patients With Primary Osteoarthritis Affecting a Single Knee

Conditions
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Osteoarthritis of the Knee

Intervention / Treatment
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* Drug: TV-45070
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is between 40 and 85 years of age, Patient has primary OA in a single knee (target knee) confirmed by American College of Rheumatology criteria. For patients taking non-steroidal anti-inflammatory drugs (NSAIDs) or other analgesics at the time of the screening visit, Patient has visual analog scale (VAS) pain scores with acceptable ranges as determined by the investigator during screening Except for OA, patient is judged by the investigator to be medically healthy and able to participate in the study. Other criteria apply, please contact the investigator for additional information Exclusion Criteria: Patient has secondary or inflammatory arthritis of the knee such as psoriasis, rheumatoid arthritis (RA), gout, other primary bone disease, or acute trauma. Patient has symptomatic chondrocalcinosis Patient has a history of fibromyalgia. Patient has any painful or disabling conditions that in the opinion of the investigator may confound assessment of pain scoring. Patient has uncontrolled cardiac, renal, hepatic or other systemic disorders that in the opinion of the investigator may jeopardize the patient. Patient has significant edema or skin disorder (including sores, rashes, or ulcers) at the target knee and surrounding area. Patient has a history of total or partial knee replacement in either leg. Patient had a major reconstructive knee surgery or arthroscopy of the target knee within 6 months before the screening visit. Patient is unable or unwilling to discontinue opioid and/or other prescription analgesics for control of OA pain. Patient is intolerant to study drug, its excipients, and/or acetaminophen. Patient uses any over the counter oral medications such as glucosamine or chondroitin sulfate products, unless the patient has been receiving the medication for ≥3 months at the time of the screening visit and maintains the medication as stable therapy for the duration of the study. Other criteria apply, please contact the investigator for additional information

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 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: TV-45070 4%<br>TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28. | Drug: TV-45070<br>* TV-45070 ointment administered twice a day (morning and evening) to target knee. Participants were provided with a laminated instruction sheet including pictures that both described and illustrated how the ointment was to be spread over the entire knee anteriorly, medially, and laterally in a thin layer that fully covered the area. The ointment was gently massaged into the skin.<br>* Other names: XEN402;|
| Experimental: TV-45070 8%<br>TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28. | Drug: TV-45070<br>* TV-45070 ointment administered twice a day (morning and evening) to target knee. Participants were provided with a laminated instruction sheet including pictures that both described and illustrated how the ointment was to be spread over the entire knee anteriorly, medially, and laterally in a thin layer that fully covered the area. The ointment was gently massaged into the skin.<br>* Other names: XEN402;|
| Placebo Comparator: Placebo<br>Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28. | Drug: Placebo<br>* Placebo ointment matching active intervention administered twice a day (morning and evening) to target knee. Participants were provided with a laminated instruction sheet including pictures that both described and illustrated how the ointment was to be spread over the entire knee anteriorly, medially, and laterally in a thin layer that fully covered the area. The ointment was gently massaged into the skin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Last 5 Days of Treatment in the Average Evening Pain Intensity In the Target Knee When Walking on a Flat Surface Using a Mixed Model for Repeated Measures (MMRM) | The Western Ontario and McMasters Universities Arthritis Index [WOMAC] is a widely used, validated, patient-reported questionnaire used to assess pain, stiffness, and physical function in patients with OA of the knee. It consists of 24 items separated into 3 domains (pain [5 items], stiffness [2 items], and physical function [17 items]). WOMAC Question 1 is the first question in the pain domain and asks patients to rate their pain in the target knee while walking on a flat surface. The possible score for each item ranges from 0 (no pain) to 100 mm (worst pain). Participants record their response to WOMAC Question 1 in the study diary based on average pain upon walking since the last assessment or over the past 12 hours. Negative change from baseline scores indicate improvement in pain. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline average evening WOMAC Question 1 score as a covariate; and patient as a random factor. | Baseline (day -5 to day -1), Last 5 days of treatment (day 24 to day 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Last 5 Days of Treatment in the Average Daily WOMAC Pain Subscale Score In the Target Knee Using a Mixed Model for Repeated Measures | The five items in the WOMAC Pain Subscale cover pain during walking, using stairs, in bed, sitting or lying, and standing. Daily WOMAC pain subscale score is calculated as the sum of the 5-item pain subscale scores (WOMAC) recorded at evening for a total range of 0 (no pain) to 500 (worst pain on all 5 items). Negative change from baseline scores indicate improvement in pain. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline average evening WOMAC scores for the 5-item pain subscale as a covariate; and patient as a random factor. | Baseline (day -5 to day -1), Last 5 days of treatment (day 24 to day 28) | 
| Change From Baseline to Last 5 Days of Treatment in the Average Morning Pain Intensity In the Target Knee When Walking on a Flat Surface Using a Mixed Model for Repeated Measures (MMRM) | The Western Ontario and McMasters Universities Arthritis Index [WOMAC] is a widely used, validated, patient-reported questionnaire used to assess pain, stiffness, and physical function in patients with OA of the knee. It consists of 24 items separated into 3 domains (pain [5 items], stiffness [2 items], and physical function [17 items]). The possible score for each item ranges from 0 (no pain) to 100 mm (worst pain). WOMAC Question 1 is the first question in the pain domain and asks patients to rate their pain in the target knee while walking on a flat surface. Participants record their response to WOMAC Question 1 in the study diary based on average pain upon walking since the last assessment or over the past 12 hours. Negative change from baseline scores indicate improvement in pain. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline average morning WOMAC Question 1 score as a covariate; and patient as a random factor. | Baseline (day -5 to day -1), Last 5 days of treatment (day 24 to day 28) | 
| Change From Baseline (Randomization Visit) to the Week 4 Visit in the WOMAC Physical Function Subscale Score for the Target Knee Using a Mixed Model for Repeated Measures | The seventeen items in the WOMAC physical function subscale cover stair use, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy household duties, light household duties. WOMAC physical function subscale score is calculated as the sum of the 17-item physical function subscale scores (WOMAC) for a total range of 0 (no pain) to 1700 (worst pain on all 17 items). Negative change from baseline scores indicate improvement in pain. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline physical function WOMAC scores for the 17-item subscale as a covariate; and patient as a random factor. | Baseline (day 1, predose), Treatment: Week 4 (day 29) | 
| Change From Baseline (Randomization Visit) to the Week 4 Visit in the WOMAC Stiffness Subscale Score for the Target Knee Using a Mixed Model for Repeated Measures | The two items in the WOMAC stiffness subscale cover stiffness after first waking and later in the day. WOMAC stiffness subscale score is calculated as the sum of the 2-item stiffness subscale scores (WOMAC) for a total range of 0 (no stiffness) to 200 (worst stiffness on both items). Negative change from baseline scores indicate improvement in stiffness. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline stiffness WOMAC scores for the 2-item subscale as a covariate; and patient as a random factor. | Baseline (day 1, predose), Treatment: Week 4 (day 29) | 
| Percentage of Participants With a >=30% and a >=50% Response in Average Evening Pain Intensity of WOMAC Question 1 in the Target Knee During the Last 5 Days of Treatment Compared With Baseline | WOMAC Question 1 is the first question in the pain domain and asks patients to rate their pain in the target knee while walking on a flat surface. The possible score for each item ranges from 0 (no pain) to 100 mm (worst pain). Average pain is calculated using a MMRM which includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline average evening WOMAC Question 1 score as a covariate; and patient as a random factor. Responder rate was calculated as 100 * the value of (average WOMAC pain subscale during the last 5 days of treatment [Days 24 to 28]) - average WOMAC pain subscale at baseline [the 5 days prior to randomization])/average WOMAC pain subscale at baseline (the 5 days prior to randomization). Participants with missing responder rates were treated as nonresponders. | Baseline (day -5 to day -1), Last 5 days of treatment (day 24 to day 28) | 
| Change From Baseline (Randomization Visit) to the Week 4 Visit in the Pain Quality Assessment Scale - Revised (PQAS-R) for the Target Knee Using a Mixed Model for Repeated Measures | PQAS-R is a standardized self-report tool that measures various aspects of a participant's pain. There are 19 questions (question 19 has 2 parts) that ask the participant to rate the various aspects (intensity, sharpness, heat, cold, etc.) of his/her pain over the past week on average on a scale of 0 to 10 (0 = not [aspect] and 10 = the most or worst imaginable [aspect]). PQAS-R score at each visit is the sum of responses for the 19 questions for a total range of 0=no pain to 200=worst imaginable pain in all aspects. Negative change from baseline scores indicate improvement in stiffness. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline PQAS-R score for the 19 questions (20 parts) as a covariate; and patient as a random factor. | Baseline (day 1, predose), Treatment: Week 4 (day 29) | 
| Participants' Global Assess of Treatment as Measured by the Patient Global Impression of Change (PGIC) at Weeks 2 and 4 Using a Mixed Model for Repeated Measures (MMRM) | PGIC is a standardized self-report tool that measures the change in a participants overall status rating since the start of treatment on 7-point scale. The 7-point scale is defined as: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. The MMRM model includes week, treatment, study center, and treatment by week interaction as the fixed factors and unconstructed variance-covariance structure. | Weeks 2 (day 15), 4 (day 29) | 
| Change From Baseline in the Patient Global Assessment (PGA) Scores at Weeks 2 and 4 Using a Mixed Model for Repeated Measures (MMRM) | PGA is a simple self-report tool for measuring the overall way arthritis is affecting the patient at a particular point in time. There is 1 question and the response is provided on a visual analog scale (VAS) from 0 (very poor) to 100 (very good). The question is: Considering all the ways your arthritis affect you, how are you feeling today? Positive change from baseline scores indicate improvement. The MMRM model includes week, treatment, study center, and treatment by week interaction as the fixed factors; baseline PGA score as a covariate and unconstructed variance-covariance structure. | Baseline (day 1, predose), Week 2 (day 15) and Week 4 (day 29) | 
| Percentage of Participants Who Are Responders Per Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) Criteria at Week 4 | Participants are classified as 'Yes' if the following criteria are met: - >=50% improvement from baseline and an absolute change >=20 on a scale of 1-100 in either the pain or physical function subscale (WOMAC). or 2 of the 3 criteria as below met: - 1) >=20% improvement from baseline and an absolute change >=10 on a scale of 1-100 in the pain subscale (WOMAC); - 2) >=20% improvement from baseline and an absolute change >=10 on a scale of 1-100 in the physical function subscale (WOMAC); - 3) at least a 20% improvement from baseline and an absolute change >=10 on a scale of 1-100 in PGA. Otherwise, 'No' The responder rate per OMERACT-OARSI criteria was analyzed using a generalized estimating equation (GEE) method, where binary variable responder rate (Yes/No) was modeled through logit link function, with treatment, center, week, and treatment*week as explanatory factors. The unstructured working correlation structure was applied. | Week 4 (day 29) | 
| Participants With Treatment-Emergent Adverse Events | An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes. | day 1 up to day 57 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoarthritis, OA, Arthritis pain