kneeosteoarthritis

The primary objective of the study is to demonstrate the efficacy of at least one dose (among 3 doses) of S201086/GLPG1972 compared to placebo after 52 weeks of treatment in reducing cartilage loss measured by cartilage thickness using qMRI of the cMTFC of the target knee. The secondary objectives are: To assess the safety and tolerability of 3 doses of S201086/GLPG1972. To assess efficacy of 3 doses of S201086/GLPG1972 versus placebo after 52 weeks of treatment on: - the proportion of “structural progressors*” based on cartilage thickness using qMRI of the cMTFC of the target knee - pain, function, and stiffness measured with WOMAC - pain measured with a 100-mm visual analog scale (VAS) - patient global assessment (PGA) of disease activity measured with 100-mm VAS - reduction of cartilage loss measured by cartilage thickness using qMRI of the total tibiofemoral compartment (tTFC) of the target knee - JSW measured by x-ray

S201086/GLPG1972

S201086/GLPG1972

Film-coated

75

The primary efficacy endpoint:
The change from baseline to W052 in cartilage thickness of the cMTFC of the target knee:
qMRI.
Secondary efficacy endpoints:
- Proportion of structural progressors* at W052 based on cartilage thickness of the
cMTFC of the target kneeqMRI
- The change from baseline to W052 in WOMAC total score and subscales scores of
the target knee for pain, function, and stiffness
- The change from baseline to W052 in pain of the target knee: 100-mm VAS
- The change from baseline to W052 in PGA of disease activity of the target knee:
100-mm VAS
- The proportion of Outcome Measures in Rheumatology (OMERACT)-OARSI
responders** at W052: defined according to WOMAC and PGA
- The change from baseline to W052 in cartilage thickness of the tTFC of the target
knee: qMRI
- The change from baseline to W028 and to W052 in bone area of the medial femoral
condyle surface of the target knee: qMRI
- The change from baseline to W052 in JSW of the target knee: X-Ray
- Pain: analgesic consumption at every visit up to W052

Inclusion criteria
All patients included should present the following characteristics:
1.a. Male patients or female patients of non-childbearing potential and not breastfeeding.
Note: Female patients will be considered of non-childbearing potential if they are either surgically sterile
(e.g. tubal ligation, hysterectomy) or postmenopausal (at least 12 consecutive months of amenorrhea in
the absence of other biological or physiological causes AND 50 years of age or older).
2. Age between 40 to 75 years (both inclusive).
3. Body weight > 40 kg.
4. Body mass index (BMI) < 40 kg/m2
.
5. Diagnosed for knee OA based on the clinical and radiological criteria of the ACR
(documented diagnosis), i.e.:
a- Knee pain
b- and, at least one of the following:
 age more than 50 years
 morning stiffness < 30 minutes duration
 crepitus on active motion
c- and, presence of osteophytes
6. History of knee pain for at least 6 months and on the majority of days (> 50%) during
the preceding month.
7. Symptom severity defined by a pain ≥ 40 mm and ≤ 90 mm on a 100 mm VAS at
screening and inclusion visits (at screening both knees should be assessed for pain and
at least one knee should fulfill pain severity defined on this criterion).
8. Documented need for symptomatic as needed-treatment for OA in the target knee with
systemic non-steroidal anti-inflammatory drugs (NSAIDs) and/or other analgesics
9.a. Disease stage based on a fixed flexion weight-bearing X-ray of the target knee* and
central read out of:
a. Predominant medial compartment radiographic disease
b. KL grade 2 or 3
c. And OARSI grade 1 or 2 medial tibiofemoral joint space narrowing (JSN)
*The target knee (right or left) to be followed-up throughout the study will be chosen as
follows:
- If both knees fulfill the clinical screening criteria (as described in Section 5.1) and
radiological inclusion criteria, the knee to be chosen should be the most severely affected
knee on X-ray (higher KL score); in case of similar KL scores, the higher JSN score will
be selected.
- If both knees display the same radiological scores, the knee to be chosen should be the
most clinically painful one (Higher VAS score at screening).
- If both knees display the same radiological scores and are equally painful, the choice
should be left to the investigator’s discretion.
10. Informed consent obtained as described in section 13.3 of the protocol.

Exclusion criteria
11. Unlikely to cooperate in the study.
12. Participation in another interventional study within 3 months before screening;
participation in non-interventional registries or epidemiological studies is allowed.
13. Re-screened patient.
14. Patient unable to understand the study.
15. Poor compliance anticipated by the investigator.
16. Investigator or other study staff or related thereof who is directly involved in the
conduct of the study.
17. Severe clinical knee malalignment according to the investigator.
18. Knee prosthesis already implanted (< 1 year) or not well-tolerated (contralateral side).
19. Knee prosthesis already foreseen within the study period (whichever side).
20. Hip prosthesis recently implanted (< 1 year) or foreseen within the study period
(whichever side).
21.a. Previous osteotomy on the inferior limbs (whichever side) other than intervention for
hallux valgus with full clinical recovery after surgery.
22.a. Any surgical operations on the target knee (arthroscopic and non-arthroscopic), other
than diagnostic arthroscopy, within the 12 months prior to the screening visit or planned
during the study period.
23.a. Diagnostic arthroscopy of the target knee within the 6 months prior to the screening
visit or planned during the study period.
24.a. Other pathologies affecting the knee such as: septic arthritis, inflammatory joint disease,
gout, major chondrocalcinosis (pseudogout), Paget’s disease of the bone, ochronosis,
acromegaly, haemochromatosis, Wilson’s disease, rheumatic symptoms due to
malignancies, primary osteochondromatosis, osteonecrosis, osteochondritis dissecans,
documented severe intra-articular knee injury (e.g. intra-articular fracture), hemophilia,
etc.
25. Generalized pain syndrome, for example fibromyalgia.
26. Chronic oral corticosteroid therapy within one month prior to enrolment into the study
other than stable doses of ≤ 7.5 mg daily prednisolone or equivalent.
27. Knee corticosteroid or hyaluronic acid intra-articular injections in the previous 3
months.
28. Use of medications with MMP-inhibitory properties (i.e. Tetracycline or structurally
related compounds) during the 3 months prior to the screening visit.
29. Bisphosphonates, Denozumab, Teriparatide and Strontium ranelate use (in oral or
injectable form) in the previous 12 months
30. Use of other unapproved drugs for osteoarthritis treatment during the 3 months prior to
the screening visit.
31.a. Chronic use of strong opioids and use of other prohibited drugs listed under section 6.6.
32. Any contraindication to MRI according to local MRI guidelines, including the inability
to undergo a knee MRI exam because of inability to fit in the scanner or knee coil.
33. Non-pharmacological standard of care (Physiotherapy, electrotherapy, etc...) if not
stable in the 4 weeks prior to the screening visit.
34. Severe or unstable disease of any type that could interfere with safety and efficacy
assessments (e.g., uncontrolled cardiovascular, pulmonary, infectious, severe immunedeficiency, autoimmune, renal, hepatic, gastro-intestinal, endocrine, blood disorders)
according to investigator’s judgment
35. History of malignancy in the past 5 years, with the exception of: basal cell carcinoma,
resected cutaneous squamous cell carcinoma in situ, prostate cancer in situ with a normal prostate-specific antigen post treatment, cervical carcinoma in situ, gastric
cancer in situ, colon cancer in situ adequately treated with no significant progression
over the past 2 years.
36. Class III or class IV Heart failure according to the New York Heart Association
(NYHA) classification.
37.a. Moderate to severe renal impairment; i.e., estimated Glomerular Filtration Rate (GFR)
< 45 mL/min/1.73 m2 (Modification of the Diet in Renal Disease [MDRD] formula).
38.a. Clinically significant abnormalities detected on a 12-lead ECG performed at screening
visit of either rhythm or conduction (e.g., QT interval corrected for HR according to
Fridericia’s formula [QTcF] interval > 450 ms for males and > 470 ms for females,
bradycardia with HR < 50 bpm, measured and stable PR > 280 ms, or second or third
degree Atrio-Ventricular Block, complete left branch block) (central reading).
39. Known severe hepatic impairment (i.e., cirrhosis, active liver disease) or known liver
enzymes abnormalities such as:
a. Aspartate aminotransferase (AST) and/or ALT values > 2 x upper limit of
normal (ULN)
b. Alkaline phosphatase (ALP) > 3 x ULN,
c. Total bilirubin > 1.5 x ULN (except in case of Gilbert syndrome)
40. Positive for hepatitis B surface antigen (HBs), anti-hepatitis C virus (HCV) antibodies
or anti-human immunodeficiency virus (HIV) antibodies
41. Severe malabsorption according to investigator’s judgment.
42. Unexplained significant weight loss (> 10% of body weight within the last year).
43. Alcohol abuse or drug abuse or addiction according to investigator’s judgment.
44.a. Hypersensitivity to the active substance or to any of the excipients (e.g.: lactose).