A Long-Term, Placebo-Controlled X-Ray Study Investigating the Safety and Efficacy of SD-6010 in Subjects With Osteoarthritis of the Knee

Study Overview
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Brief Summary
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The objective of this 2-year study is to evaluate the safety, tolerability and disease modifying efficacy of SD 6010, an inhibitor of inducible nitric oxide synthase (iNOS), in overweight and obese subjects with knee osteoarthritis. The efficacy of SD-6010 will be evaluated by radiography using joint space narrowing in the medial tibiofemoral compartment of the study knee as the primary endpoint.

Official Title
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A Long-Term, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Radiographic Study To Investigate The Safety And Efficacy Of Orally Administered SD-6010 In Subjects With Symptomatic Osteoarthritis Of The Knee

Conditions
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Osteoarthritis

Intervention / Treatment
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* Drug: SD-6010
* Drug: SD-6010
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects aged >= 40 years with a BMI >= 25 and <= 40 kg/m2 In the past, has been diagnosed with knee OA Radiographic evidence of OA in the study knee Exclusion Criteria: A diagnosis of any other rheumatic disease Current conditions in the study knee that would confound efficacy Selected, traditional clinical safety and laboratory parameters

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 99 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 |
| --- | --- |
| Active Comparator: 200 mg<br>High dose active comparator | Drug: SD-6010<br>* 200 mg tablets once a day for 2 years<br>|
| Active Comparator: 50 mg<br>Low dose active comparator | Drug: SD-6010<br>* 50 mg tablets once a day for 2 years<br>|
| Placebo Comparator: Placebo<br>Placebo comparator to be used for control purposes | Drug: Placebo<br>* Placebo tablets once a day for 2 years<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Progression of Joint Space Narrowing | Rate of progression of joint space narrowing (JSN) was defined as narrowing in joint space width (JSW) over the course of the study. It was measured radiographically in the medial tibiofemoral of knee of participants with OA. The slope reported in millimeter per year (mm/year) over a 2 year period was used to assess the rate of progression of JSN. Negative values indicating a worsening of osteoarthritis. | Baseline up to Month 24 | 
| Rate of Progression of Joint Space Narrowing in Participants With Kellgren and Lawrence Grade Less Than or Equal to (<=) 2 | Rate of progression of JSN was defined as narrowing in joint space width over the course of the study. It was measured radiographically in the medial tibiofemoral of knee of participants with OA. The slope reported in mm/year over a 2 year period was used to assess the rate of progression of JSN. KLG system was a method of classifying the severity of knee OA using five grades (0 [no severity] to 4 [maximum severity], higher grade indicating worse knee function). Negative values of slope indicating a worsening of osteoarthritis. | Baseline up to Month 24 | 
| Rate of Progression of Joint Space Narrowing in Participants With Kellgren and Lawrence Grade Equal to (=) 3 | Rate of progression of JSN was defined as narrowing in joint space width over the course of the study. It was measured radiographically in the medial tibiofemoral of knee of participants with OA. The slope reported in mm/year over a 2 year period was used to assess the rate of progression of JSN. KLG system was a method of classifying the severity of knee OA using five grades (0 [no severity] to 4 [maximum severity], higher grade indicating worse knee function). Negative values of slope indicating a worsening of osteoarthritis. | Baseline up to Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Western Ontario and MacMaster Osteoarthritis Index (WOMAC) Composite Index Score at Month 3, 6, 12, 18 and 24 | The WOMAC was a self-administered, disease-specific instrument which probed clinically important, participant relevant symptoms in the areas of pain, stiffness, and physical function in participants with OA of the knee. The WOMAC composite index was the sum of 24 individual questions regarding subscales of pain, stiffness and physical function (for each item score range: 0 [minimum] to 4 [maximum], higher score indicating worse knee condition). Total score was sum of the 3 subscale scores, giving a possible overall score range of 0 (minimum) to 96 (maximum). Higher score indicating the worse level of pain, stiffness and physical function. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Western Ontario and MacMaster Osteoarthritis Index Pain Subscale Score at Month 3, 6, 12, 18 and 24 | The WOMAC pain subscale was comprised of 5 questions regarding the amount of pain experienced due to OA in the study knee. The WOMAC pain subscale score for each question ranged from 0 (minimum) to 4 (maximum), higher scores signified worse pain. An overall subscale score range of 0 (minimum) to 20 (maximum), with higher scores indicating more pain. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Western Ontario and MacMaster Osteoarthritis Index Pain Stiffness Subscale Score at Month 3, 6, 12, 18 and 24 | Stiffness was defined as a sensation of decreased ease in which the participant moved the knee with OA. The WOMAC stiffness subscale was comprised of 2 questions regarding the degree of stiffness experienced in the study knee. The WOMAC stiffness subscale score for each question ranged from 0 (minimum) to 4 (maximum), higher scores signified worse stiffness. An overall score range of 0 (minimum) to 8 (maximum), with higher scores indicating more stiffness. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Western Ontario and MacMaster Osteoarthritis Index Physical Function Subscale Score at Month 3, 6, 12, 18 and 24 | The WOMAC physical function subscale referred to the participant's ability to move around and perform usual activities of daily living. The WOMAC physical function subscale was comprised of 17 questions regarding the degree of difficulty experienced due to OA in the study knee. The WOMAC physical function subscale score for each question ranged from 0 (minimum) to 4 (maximum), higher scores signified worse physical function. An overall score range of 0 (minimum) to 68 (maximum), with higher scores indicating worse physical function. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Patient Assessment of Arthritic Pain Visual Analog Scale (VAS) Score at Month 3, 6, 12, 18 and 24 | Pain VAS was a self-administered instrument, a 100 millimeter (mm) line marked by participant. Intensity of pain range (over past week): 0 (mm) =no pain to 100 (mm) =worst possible pain. Higher score indicating severe pain. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Patient Global Assessment of Arthritic Condition Score at Month 3, 6, 12, 18 and 24 | Participants answered: Considering all the ways your arthritis affects you, how are you feeling today? Participants responded by using the scale ranging from 1 (minimum) to 5 (maximum), where 1 =very good, 2 =good, 3 =fair, 4 =poor and 5 =very poor. Higher scores indicating worse condition. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Physician's Global Assessment of Arthritic Condition Score at Month 3, 6, 12, 18 and 24 | Physician assessed the overall impact of arthritis on the participant's daily life. Participant's condition was rated by the physician using the scale ranging from 1 (minimum) to 5 (maximum), where 1= very good, 2= good, 3= fair, 4= poor and 5= very poor. Higher scores indicating worse condition. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Pain After a 50-foot Walk Using Pain Visual Analog Scale Score at Month 3, 6, 12, 18 and 24 | The pain VAS following a 50 foot walk was a single-item, self-administered instrument. Participants were asked to assess the pain due to OA in their study knee after a 50-foot walk. Participants responded on a VAS scale ranging from 0 (no pain) to 100 (severe pain). Higher scores indicating more pain. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Osteoarthritis Pain Assessment Tool-Knee Joint Total Score at Month 3, 6, 12, 18 and 24 | The OA pain and assessment tool-knee joint is also known as the intermittent and constant osteoarthritis pain (ICOAP) scale. The OA pain assessment tool-knee joint was an 11-item scale, with each item scored from 0 (minimum) to 4 (maximum), where 4 indicated worst health condition. The total score was calculated by adding the 11 items and rescaled to a 0 (minimum) to 100 (maximum) scale, where higher scores indicating worse health. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Osteoarthritis Pain Assessment Tool-Knee Joint Constant Pain Subscale Score at Month 3, 6, 12, 18 and 24 | The OA pain assessment tool-knee joint constant pain subscale was a 5 item scale, with each item scored from 0 (minimum) to 4 (maximum), where 4 indicated worst health condition. Overall subscale score was calculated by adding the 5 items and rescaled to a 0 (minimum) to 100 (maximum) scale, where higher scores indicating worse constant pain. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Osteoarthritis Pain Assessment Tool-Knee Joint Intermittent Pain Subscale Score at Month 3, 6, 12, 18 and 24 | The OA pain assessment tool-knee joint intermittent pain subscale score a 6 item scale, with each item scored from 0 (minimum) to 4 (maximum), where 4 indicated worst health condition. Overall subscale score was calculated by adding the 6 items and rescaled to a 0 (minimum) to 100 (maximum) scale, where higher scores indicating worse intermittent pain. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Osteoarthritis Research Society International (OARSI) Knee Function Survey Score at Month 3, 6, 12, 18 and 24 | The OARSI knee function survey was an 11-item scale with each item scored 0 (minimum) to 4 (maximum), where 4 indicated worst health condition. The total score was the sum of the 11 items and ranged from 0 (minimum) to 44 (maximum), where higher scores indicating worse health condition. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Knee Injury and Osteoarthritis Outcome Score - Physical Function Short Form (KOOS-PS) Score at Month 3, 6, 12, 18 and 24 | The KOOS-PS was used to rate participant's opinions about the difficulties they experienced with activity due to problems with their knee. It was a 7-item scale, each item scored from 0 (minimum) to 4 (maximum), where 4 indicated worst health condition. Total score was calculated by adding the responses to 7 items and rescaled to a 0 (minimum) to 100 (maximum) scale, where higher scores indicating worse health condition. | Baseline, Month 3, 6, 12, 18, 24 | 
| Change From Baseline in Short Form-36 (SF-36) Physical Functioning Domain Score at Month 12 and 24 | The SF-36 was a participant administered scale assessing general quality of life. It consisted of self-administered 36-item questionnaire that measured 8 health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. These 8 domains were also summarized as physical and mental component scores. The score for each domain and component score was the mean of the individual question scores, which were scaled from 0 (minimum) to 100 (maximum), where higher scores indicated highest level of health/functioning. Linear transformations were performed to transform scores and rescaled to a score range of 16.18 (minimum) to 57.11 (maximum), with higher scores indicating better physical functioning. | Baseline, Month 12, 24 | 
| Change From Baseline in Short Form-36 Role - Physical Domain Score at Month 12 and 24 | The SF-36 was a participant administered scale assessing general quality of life. It consisted of self-administered 36-item questionnaire that measured 8 health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. These 8 domains were also summarized as physical and mental component scores. The score for each domain and component score was the mean of the individual question scores, which were scaled from 0 (minimum) to 100 (maximum), where higher scores indicated highest level of health/functioning. Linear transformations were performed to transform scores and rescaled to a score range of 18.45 (minimum) to 56.62 (maximum), with higher scores indicating better role-physical. | Baseline, Month 12, 24 | 
| Change From Baseline in Short Form-36 Bodily Pain Domain Score at Month 12 and 24 | The SF-36 was a participant administered scale assessing general quality of life. It consisted of self-administered 36-item questionnaire that measured 8 health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. These 8 domains were also summarized as physical and mental component scores. The score for each domain and component score was the mean of the individual question scores, which were scaled from 0 (minimum) to 100 (maximum), where higher scores indicated highest level of health/functioning. Linear transformations were performed to transform scores and rescaled to a score range of 19.23 (minimum) to 60.88 (maximum), with higher scores indicating lower bodily pain. | Baseline, Month 12, 24 | 
| Change From Baseline in Short Form-36 General Health Domain Score at Month 12 and 24 | The SF-36 was a participant administered scale assessing general quality of life. It consisted of self-administered 36-item questionnaire that measured 8 health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. These 8 domains were also summarized as physical and mental component scores. The score for each domain and component score was the mean of the individual question scores, which were scaled from 0 (minimum) to 100 (maximum), where higher scores indicated highest level of health/functioning. Linear transformations were performed to transform scores and rescaled to a score range of 16.75 (minimum) to 63.72 (maximum), with higher scores indicating better general health. | Baseline, Month 12, 24 | 
| Change From Baseline in Short Form-36 Vitality Domain Score at Month 12 and 24 | The SF-36 was a participant administered scale assessing general quality of life. It consisted of self-administered 36-item questionnaire that measured 8 health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. These 8 domains were also summarized as physical and mental component scores. The score for each domain and component score was the mean of the individual question scores, which were scaled from 0 (minimum) to 100 (maximum), where higher scores indicated highest level of health/functioning. Linear transformations were performed to transform scores and rescaled to a score range of 22.02 (minimum) to 69.92 (maximum), with higher scores indicating better vitality. | Baseline, Month 12, 24 | 
| Change From Baseline in Short Form-36 Social Functioning Domain Score at Month 12 and 24 | The SF-36 was a participant administered scale assessing general quality of life. It consisted of self-administered 36-item questionnaire that measured 8 health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. These 8 domains were also summarized as physical and mental component scores. The score for each domain and component score was the mean of the individual question scores, which were scaled from 0 (minimum) to 100 (maximum), where higher scores indicated highest level of health/functioning. Linear transformations were performed to transform scores and rescaled to a score range of 13.38 (minimum) to 56.40 (maximum), with higher scores indicating better social functioning. | Baseline, Month 12, 24 | 
| Change From Baseline in Short Form-36 Role-Emotional Domain Score at Month 12 and 24 | The SF-36 was a participant administered scale assessing general quality of life. It consisted of self-administered 36-item questionnaire that measured 8 health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. These 8 domains were also summarized as physical and mental component scores. The score for each domain and component score was the mean of the individual question scores, which were scaled from 0 (minimum) to 100 (maximum), where higher scores indicated highest level of health/functioning. Linear transformations were performed to transform scores and rescaled to a score range of 10.25 (minimum) to 55.68 (maximum), with higher scores indicating better role-emotional. | Baseline, Month 12, 24 | 
| Change From Baseline in Short Form-36 Mental Health Domain Score at Month 12 and 24 | The SF-36 was a participant administered scale assessing general quality of life. It consisted of self-administered 36-item questionnaire that measured 8 health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. These 8 domains were also summarized as physical and mental component scores. The score for each domain and component score was the mean of the individual question scores, which were scaled from 0 (minimum) to 100 (maximum), where higher scores indicated highest level of health/functioning. Linear transformations were performed to transform scores and rescaled to a score range of 8.02 (minimum) to 63.43 (maximum), with higher scores indicating better mental health. | Baseline, Month 12, 24 | 
| Change From Baseline in Short Form-36 Physical Health Component Score at Month 12 and 24 | The SF-36 was a participant administered scale assessing general quality of life. It consisted of self-administered 36-item questionnaire that measured 8 health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. These 8 domains were also summarized as physical and mental component scores. The score for each domain and component score was the mean of the individual question scores, which were scaled from 0 (minimum) to 100 (maximum), where higher scores indicated highest level of health/functioning. Linear transformations were performed to transform scores and rescaled to a score range of 22.88 (minimum) to 58.69 (maximum), with higher scores indicating better physical health. | Baseline, Month 12, 24 | 
| Change From Baseline in Short Form-36 Mental Health Component Score at Month 12 and 24 | The SF-36 was a participant administered scale assessing general quality of life. It consisted of self-administered 36-item questionnaire that measured 8 health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. These 8 domains were also summarized as physical and mental component scores. The score for each domain and component score was the mean of the individual question scores, which were scaled from 0 (minimum) to 100 (maximum), where higher scores indicated highest level of health/functioning. Linear transformations were performed to transform scores and rescaled to a score range of 11.11 (minimum) to 61.67 (maximum), with higher scores indicating better mental health. | Baseline, Month 12, 24 | 
| Number of Participants With EuroQoL-5D (EQ-5D) Mobility Domain Score | EQ-5D: participant rated questionnaire to assess health-related quality of life. Health state profile component assessed level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, anxiety and depression. EQ-5D mobility domain score scale ranged from 1 (minimum) to 3 (maximum), where 1 =better health (no problem), 2 =moderate health (some problems) and 3 =worst health (confined to bed). Higher scores indicating worse health condition. Participants with EQ-5D mobility domain score were reported in this measure. | Baseline, Month 12, 24 | 
| Number of Participants With EuroQoL-5D Self-Care Domain Score | EQ-5D: participant rated questionnaire to assess health-related quality of life. Health state profile component assessed level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, anxiety and depression. EQ-5D self-care domain score scale ranged from 1 (minimum) to 3 (maximum), where 1 =better health (no problems with self-care), 2 =moderate health (some problems) and 3 =worst health (unable to wash or dress). Higher scores indicating worse health condition. Participants with EQ-5D self-care domain score were reported in this measure. | Baseline, Month 12, 24 | 
| Number of Participants With EuroQoL-5D Usual Activity Domain Score | EQ-5D: participant rated questionnaire to assess health-related quality of life. Health state profile component assessed level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, anxiety and depression. EQ-5D usual activity domain score scale ranged from 1 (minimum) to 3 (maximum), where 1 =better health (no problems), 2 =moderate health (some problems) and 3 =worst health state (unable to perform usual activities). Higher scores indicating worse health condition. Participants with EQ-5D usual activity domain score were reported in this measure. | Baseline, Month 12, 24 | 
| Number of Participants With EuroQo-5D Pain and Discomfort Domain Score | EQ-5D: participant rated questionnaire to assess health-related quality of life. Health state profile component assessed level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, anxiety and depression. EQ-5D pain and discomfort domain score scale ranged from 1 (minimum) to 3 (maximum), where 1 =better health (no pain and discomfort), 2 =moderate health (moderate pain and discomfort) and 3 =worst health state (extreme pain and discomfort). Higher scores indicated worse health condition. Participants with EQ-5D pain and discomfort domain score were reported in this measure. | Baseline, Month 12, 24 | 
| Number of Participants With EuroQoL-5D Anxiety and Depression Domain Score | EQ-5D: participant rated questionnaire to assess health-related quality of life. Health state profile component assessed level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. EQ-5D anxiety and depression domain score scale ranged from 1 (minimum) to 3 (maximum), where 1 =better health (not anxious, depressed), 2 =moderate health (moderately anxious, depressed) and 3 =worst health (extremely anxious, depressed). Higher scores indicating worse health condition. Participants with EQ-5D anxiety and depression domain score were reported in this measure. | Baseline, Month 12, 24 | 
| EuroQoL-5D Visual Analog Scale Score | The EQ-5D VAS score was a participant rated questionnaire to assess health-related quality of life in terms of a single index value. It was a visual analogue scale that ranged from 0 (minimum) to 100 (maximum), with higher scores indicating a better health condition. | Baseline, Month 12, 24 | 
| Number of Participants With Increase in Total Analgesic Medication Use | Increase in total analgesic medication use for OA in the study knee was a comparison back to baseline of an increased and sustained use of standard background and/or rescue medication for more than 28 days as measured at the Month 12 and 24 visits. Only medications for OA knee pain were considered. | Month 12, 24 | 
| Number of Participants With Decrease in Total Analgesic Medication Use | Decrease in total analgesic medication use for OA in the study knee was a comparison back to baseline of a decreased and irregular use of standard background and/or rescue medication for more than 28 days as measured at the Month 12 and 24 visits. Only medications for OA knee pain were considered. | Month 12, 24 | 
| Patient Global Impression of Change Score | Patient global impression of change was a participant-rated instrument that measured change in participant's overall status on a 7-point scale ranging from: 1 =very much improved, 2 =much improved, 3 =minimally improved, 4 =no change, 5 =minimally worse, 6 =much worse and 7 =very much worse. Higher scores indicating worse condition. | Month 24 | 
| Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) Responder Index | The OMERACT-OARSI responder index was used to determine whether participants may be considered responders to treatment. An OMERACT-OARSI responder was a participant who had a better response on the WOMAC pain subscale score, a better response on the WOMAC physical function subscale score or improvement on at least two of the three domains: WOMAC pain subscale score (overall score range of 0 [minimum] to 20 [maximum], higher scores indicating more pain), WOMAC physical function subscale score (overall score range of 0 [minimum] to 68 [maximum], higher scores indicating worse physical function) and patient global assessment of arthritic condition score (overall score range of 1 [minimum] to 5 [maximum], higher scores indicating worse condition). Number of participants who were OMERACT-OARSI responder were reported in this measure. | Month 24 | 
| Number of Participants With Joint Space Narrowing Progression | JSN progressor was defined as a participant with a decrease in joint space width that was greater in magnitude than the smallest detectable difference (0.199 mm). | Month 24 | 
| Number of Participants Applicable for Virtual Joint Replacement | A virtual joint replacement candidate was defined as a participant whose last two WOMAC pain subscale scores (overall score range of 0 [minimum] to 20 [maximum], higher scores indicating more pain) were at least 8, last two WOMAC physical function subscale scores (overall score range of 0 [minimum] to 68 [maximum], higher scores indicating worse physical function) were at least 28 and was a joint space narrowing progressor (a participant with a decrease in JSW that was greater in magnitude than the smallest detectable difference =0.199 mm). | Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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knee Osteoarthritis Disease Modifying Osteoarthritis Drug