E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Osteo Arthritis of the knee |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10023476 |
E.1.2 | Term | Knee osteoarthritis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the disease modifying efficacy of SD-6010 50 mg and 200 mg QD compared to placebo in reducing the rate of progression of OA as assessed by radiographic JSN in the medial tibiofemoral compartment of the study knee of subjects with knee OA. |
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E.2.2 | Secondary objectives of the trial |
1. To assess the safety and tolerability of SD-6010 50 mg and 200 mg QD administered long-term to subjects with knee OA;
2.To assess the clinical benefit of SD-6010 50 mg and 200 mg QD in subjects
with knee OA as measured by the clinical endpoints including, but not limited to,
WOMAC, pain VAS (visual analog scale), changes in background pain therapy and
use of rescue medication in the study knee. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Investigator Level Assessments for Inclusion
1. Has provided written informed consent and is willing to comply with scheduled visits, treatment plan, radiographs, laboratory tests, and other trial procedures;
2.Age ≥40 years with a BMI ≥25 and ≤40 kg/m2;
3. In the past, has been diagnosed with knee OA and has had knee symptoms in the past year defined as:
• Pain, aching or stiffness on most days of a month; and/or
• Used a medication (other than potent opioids) for treatment of knee pain on most days of a month;
4.If currently being treated for OA knee symptoms, has been on the same standard of care medication(s) and on a stable dosing regimen for at least 4 weeks preceding the first dose of study medication (stable defined as: Doses and frequency of administration remain unchanged);
6. If female, is of non-childbearing potential, if 1 of the 2 categories below is satisfied:
• Is ≥45 years of age and amenorrheic for at least 2 years, or
• Has proof of a physician documented hysterectomy and/or bilateral oophorectomy;
Note: Females not meeting the non-childbearing rules above or having undergone tubal ligation will be considered of childbearing potential for this study (refer to #6 next).
6.If a male, or a female of childbearing potential, has agreed that when sexually active, to use the protocol designated effective methods of contraception and abide by the time frames described in Sections 4.5.1.1 and 4.5.1.2;
Central Imaging Core Laboratory Criteria for Inclusion
Subjects meeting the following Screen 1 inclusion criteria by radiography as assessed through the modified Lyon-schuss X-ray will be semi-qualified for Screen 2. Criteria 1 4 below will be assessed by the independent Central Reader from data from the Central Imaging Core Laboratory for determining which subjects will be invited back for Screen 2.
A “yes” answer to each criterion is needed to continue screening.
1. A KLG 2 or 3 AND a medial tibiofemoral minimum JSW ≥2 mm and more narrowed than the lateral JSW in the study knee;
2. KLG <4 in the contralateral knee; unless the contralateral knee has KLG 4 changes and, in the opinion of the Investigator, the subject is unlikely to undergo arthroplasty within the next 2 years, the subject will be considered for eligibility. Conversely, if a subject is at risk of becoming incapacitated in the near future due to the KLG 4 changes such that activities of daily living are severely curtailed, the subject should not be considered for the trial.
3.An anatomic axis angle (AAA) between 184 and 174inclusive. If the study knee has KLG 3 changes and a medial JSW smaller than the lateral JSW with an AAA >184 degrees, and if the other radiographic eligibility criteria are met, the subject will be considered for eligibility;
4. No radiological findings such as, but not limited to avascular necrosis, fracture, infection, gout, Paget’s disease, osteopetrosis, osteochondritis, or other pathologies in the study knee. |
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E.4 | Principal exclusion criteria |
1. Subjects with a history of:
a. A diagnosis of any other rheumatic disease (eg, spondyloarthropathies, rheumatoid arthritis, systemic lupus erythematosus );
b. Severe, uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, neurological disease, or any other condition which would make the subject unsuitable for the study within 6 months preceding the Screen 1 visit.
c. Uncontrolled diabetes, uncontrolled hyperglycemia, active foot wound infection, or a history of diabetic ulceration;
d. Clinically significant infections (acute infection or those requiring hospitalization or requiring parenteral antimicrobial therapy) within 6 month preceding the Screen 1 visit;
e. An active malignancy of any type or history of a malignancy (with the exception of subjects with malignancy surgically removed with no evidence of recurrence within the past 5 years, and with the exception of subjects with a history of treated nonmelanoma carcinoma);
f.Any diseases or conditions involving the knees including, but not limited:
•Crystalline disease (eg, gout, pseudogout; however, mild to moderate asymptomatic chondrocalcinosis is not an exclusion).
•Endocrinopathies (eg, acromegaly)
•Metabolic diseases (eg, ochronosis, hemochromatosis, Wilson’s disease, Gaucher’s disease)
•Septic arthritis
•Neuropathic disorders
•Mechanical disorders (eg, hypermobility)
•Avascular necrosis
•Intra articular fracture
•Microfractures, cartilage debridement, chondrocyte transplantation, mosaicplasty
•Osteotomy, arthroplasty, osteophyte resection,
•Paget’s disease, tumors, (eg, primary osteochondromatosis) or collagen gene mutations
•Any injury/trauma of the knee resulting in anterior cruciate ligament (ACL)/posterior cruciate ligament (PCL) rupture or reconstruction and/or partial or total meniscectomy for traumatic meniscal tears; however, a partial or total meniscectomy for degenerative meniscal tears related to OA is not exclusionary.
g. Significant trauma to the knees including significant injury to ligaments or menisci of the knee within 1 year preceding the Screen 1 visit;
h. Alcoholism or drug abuse within 1 year preceding the Screen 1 visit;
2. Subjects presenting with:
a. A verified systolic blood pressure >150 mm Hg (if untreated for hypertension) or greater than 160 mm Hg (if treated for hypertension) and/or a diastolic blood pressure greater than 90 mm Hg;
b. Any morbidities (eg, coronary heart disease, hypertension, dyspnea, diabetes, obesity, COPD, emphysema, depression, severe OA) that would curtail work-related or leisure time physical activities (eg, walking, cooking, gardening, standing) such that these morbidities would contribute to increases in sedentary behaviors(eg, becoming chair or bed ridden, aka, “couch potato lifestyle”);
c. Chronic potent opioid use use for OA of the knees (propoxyphene, tramadol, codeine use is acceptable);
d. Any condition possibly affecting oral drug absorption (eg, gastrectomy or clinically significant diabetic gastroenteropathy);
e. Anticipated need for knee or hip surgery in the next 2 years;
f. Exacerbation of OA pain (eg, a flare) in either knee requiring a change in stable treatment within 4 weeks of the Screen 1 visit;
g. Symptomatic OA of either hip by history or elicited on physical examination that may confound the interpretation of knee pain;
2. Use of any investigational drug within 1 month preceding the Screen 1 visit;
3. Pregnant or breastfeeding females;
4. Anticipating a move out of the area of the clinic in the next 2 years.
5. A subject anticipating procedure (eg, gastric [bypass, banding, balloon], liposuction) for significant weight loss in the next 2 years or having undergone such a procedure in the last 3 months. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The progression rate of Joint space narrowing (JSN) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation of Joint Space Narrowing of the knee compartment by radiographs collected at Baseline, Month-12, and Month-24 |
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E.5.2 | Secondary end point(s) |
To asses clinical benefit of SD-6010 in subjects with knee OA through various Patient Reported Outcomes and Investigation Evaluations as well as changes in background pain therapy and use of rescue medications in the study knee.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessments made at Baseline, Week 2, Month-1, Month-3, Month-6, Month-9, Month-12, Month-15, Month-18, Month-21, Month-24, and follow-up visit at Month-25 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability, clinical benefit, analysis of IMP effect on OA progression |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Belgium |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Mexico |
Peru |
Poland |
Russian Federation |
Slovakia |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of Trial in a Member State of the European Union is defined as the time at which it is deemed that sufficient subjects have been recruited and completed the study as stated in the regulatory application (ie, Clinical Trial Application [CTA]) and ethics application in the Member State. Poor recruitment (recruiting less than the anticipated number in the CTA) by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |