A Study to Assess Efficacy and Safety of GLPG1972/S201086 in Participants With Knee Osteoarthritis (Roccella)

• ClinicalTrials.gov Identifier: NCT03595618
• Recruitment Status: Completed
• First Posted: July 23, 2018
• Results First Posted: May 12, 2021
• Last Update Posted: July 28, 2021
• Sponsor: Galapagos NV
• Collaborator: Institut de Recherches Internationales Servier
• Information provided by (Responsible Party): Galapagos NV

Tracking Information

• First Submitted Date: July 11, 2018
• First Posted Date: July 23, 2018
• Results First Submitted Date: April 20, 2021
• Results First Posted Date: May 12, 2021
• Last Update Posted Date: July 28, 2021
• Actual Study Start Date: August 14, 2018
• Actual Primary Completion Date: July 14, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 27, 2021)

Change From Baseline in Cartilage Thickness of the cMTFC as Assessed by qMRI on the Target Knee to Week 52 [ Time Frame: Baseline, Week 52 ]

Reduction in cartilage loss was assessed by cartilage thickness as measured in the medial cMTFC of the target knee using qMRI.

Original Primary Outcome Measures (submitted: July 20, 2018)

Change from baseline in cartilage thickness of the central medial tibiofemoral compartment (cMTFC) assessed by quantitative MRI on the target knee. [ Time Frame: Between Week 0 and Week 52 ]

To demonstrate the efficacy of at least one dose (among 3 doses) of S201086/GLPG1972 compared to placebo in reducing cartilage loss measured by cartilage thickness of the cMTFC of the target knee.

Current Secondary Outcome Measures (submitted: July 27, 2021)

• Number of Participants Who Were Osteoarthritis (OA) Structural Progressors Based on Cartilage Thickness in the cMTFC Assessed by qMRI on the Target Knee [ Time Frame: Week 52 ]
  A "structural progressor" was defined as a participant who had an 8% cartilage loss in cMTFC. Number of participants who met the criteria of "structural progressor" at Week 52 are provided.
• Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Total Score and Subscales Scores for Pain, Function, and Stiffness to Week 52 [ Time Frame: Baseline, Week 52 ]
  Western Ontario and McMaster Universities Osteoarthritis Index is a questionnaire designed to assess health status and health outcomes in participants with OA of the knee. The questionnaire contains 24 questions targeting areas of pain, stiffness, and physical function. Pain subscale includes 5 items rated on a Likert scale of 0 (none) to 4 (extreme) with a total range of 0-20 with higher scores indicating worse symptoms and function. Stiffness subscale includes 2 items rated on a Likert scale of 0 (none) to 4 (extreme) with a total range of 0-8 with higher scores indicating worse symptoms and function. Physical function subscale includes 17 items rated on a Likert scale of 0 (none) to 4 (extreme) with a total range of 0-68 with higher scores indicating worse symptoms and function. The total score is the sum of all subscales (range: 0 to 96) with higher scores indicating worse symptoms and function.
• Change From Baseline in Pain Assessment in the Target Knee as Measured by Visual Analog Scale (VAS) to Week 52 [ Time Frame: Baseline, Week 52 ]
  The participant was asked "how would you rate the pain felt in the selected knee within the last 48 hours?". The participants rated the pain by marking the level of pain on a 100-mm VAS, with 0 being no pain and 100 being extreme pain. Higher score indicated higher pain intensity.
• Change From Baseline in Patient Global Assessment (PGA) of Disease Activity as Measured by VAS to Week 52 [ Time Frame: Baseline, Week 52 ]
  The participant was asked "Considering all the ways in which your knee osteoarthritis affects you, please rate on this 100 mm scale how well you are doing today". The participants rated the disease activity by marking on a 100-mm VAS, with 0 being no pain and 100 being extreme pain. Higher score indicated higher disease activity.
• Number of Participants Who Were Responders Based on the Outcome Measures in Rheumatology - Osteoarthritis Research Society International (OMERACT-OARSI) Criteria [ Time Frame: Week 52 ]
  OMERACT-OARSI criteria involves improvement based on WOMAC pain and function subscales and PGA. The responders according to OMERACT-OARSI criteria were participants who had:

  • A high improvement in pain or in function ≥ 50% and absolute change ≥ 20, OR
  • Improvement in at least 2 of the 3 following:
    • Pain ≥ 20% and absolute change ≥ 10
    • Function ≥ 20% and absolute change ≥ 10
    • Patient's global assessment ≥ 20% and absolute change ≥ 10.

  WOMAC pain subscale score: range of 0 to 20, higher scores indicating more pain, WOMAC physical function subscale score: range of 0 to 68, higher scores indicating worse physical function), PGA: The participant was asked "Considering all the ways in which your knee osteoarthritis affects you, please rate on this 100 mm scale how well you are doing today". The participants rated disease activity by marking on a 100-mm VAS, with 0 being no pain and 100 being extreme pain. Higher score indicated higher disease activity.
• Change From Baseline in Cartilage Thickness of the Total Tibiofemoral Compartment (tTFC) of the Target Knee by qMRI to Week 52 [ Time Frame: Baseline, Week 52 ]
  Reduction of cartilage loss was measured by cartilage thickness of the tTFC of the target knee using qMRI.
• Change From Baseline in Bone Area of the Medial Femoral Condyle Surface of the Target Knee by qMRI to Week 28 [ Time Frame: Baseline, Week 28 ]
• Change From Baseline in Bone Area of the Medial Femoral Condyle Surface of the Target Knee by qMRI to Week 52 [ Time Frame: Baseline, Week 52 ]
• Change From Baseline in Joint Space Width (JSW) of the Target Knee to Week 52 [ Time Frame: Baseline, Week 52 ]
  The JSW is the space measured between the 2 bones in the knee joint and this is assessed by x-ray.
• Number of Participants Who Have Used at Least 1 Systemic Analgesic During the Study [ Time Frame: Baseline up to Week 52 ]
  Systemic analgesics included anti-inflammatory and anti-rheumatic products; analgesics; anti-diarrheals, intestinal, anti-inflammatory/anti-infective agents; and drugs for functional gastrointestinal disorders.
• Plasma Concentrations of GLPG1972 [ Time Frame: Pre-dose at Weeks 4, 12, and 52; Pre-dose and one post-dose sample (2-4 hours interval) at Week 28; one post dose sample (interval 4-8 hours) at Week 40 ]
• Number of Participants With Treatment-emergent Adverse Event (TEAE) [ Time Frame: Baseline up to 2-weeks after last dose of IMP (up to Week 54) ]
  TEAEs were defined as all adverse events (AEs) that occurred:

  • between first IMP intake date (included) and last visit of participant, or
  • before first IMP intake date and that worsened (in terms of intensity) or became serious according to investigator opinion between first IMP intake date (included) and last visit of participant.

  Number of participants with at least 1 TEAE (serious or non-serious) are reported.

Original Secondary Outcome Measures (submitted: July 20, 2018)

• Proportion of OA structural progressors based on cartilage thickness in the central medial tibiofemoral compartment (cMTFC) assessed by quantitative MRI on the target knee. [ Time Frame: 52 weeks ]
  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 in the CMTFC assessed of the target knee. A structural progressor is defined as a patient who had at least 8% cartilage loss in the cMTFC between baseline and Week 52.
• Change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales scores for pain, function, and stiffness. [ Time Frame: Between Week 0 and Week 52 ]
  To assess efficacy of 3 doses of S201086/GLPG1972 versus placebo after 52 weeks on iso of pain, function, and stiffness measured with WOMAC.
• Change from baseline in pain in the target knee measured with a 100-mm visual analog scale (VAS). [ Time Frame: Between Week 0 and Week 52 ]
  To assess efficacy of 3 doses of S201086/GLPG1972 versus placebo after 52 weeks of treatment on pain measured with a 100-mm visual analog scale (VAS).
• Change from baseline in patient global assessment (PGA) of disease activity measured with 100-mm visual analog scale (VAS). [ Time Frame: Between Week 0 and Week 52 ]
  To assess efficacy of 3 doses of S201086/GLPG1972 versus placebo after 52 weeks of treatment on patient PGA of disease activity measured with 100-mm VAS.
• Proportion of OMERACT-OARSI responders. [ Time Frame: Week 52 ]
  Based on OMERACT-OARSI Initiative: Osteoarthritis Research Society International set of responder criteria for OA clinical trials revisited Pham et al. 2004. A responder is defined according to WOMAC and PGA as a patient who had a high improvement in pain or in function ≥ 50% and absolute change ≥ 20 or, improvement in at least 2 of the 3 following:

  • Pain ≥ 20% and absolute change ≥ 10
  • Function ≥ 20% and absolute change ≥ 10
  • Patient's global assessment ≥ 20% and absolute change ≥ 10.
• Change from baseline in cartilage thickness of the total tibiofemoral compartment (tTFC) of the target knee by quantitative MRI. [ Time Frame: Between Week 0 and Week 52. ]
  To assess efficacy of 3 doses of S201086/GLPG1972 versus placebo after 52 weeks of treatment on reduction of cartilage loss measured by cartilage thickness using quantitative MRI of the total tibiofemoral compartment (tTFC) of the target knee.
• Change from baseline in bone area of the medial femoral condyle surface of the target knee by quantitative MRI. [ Time Frame: Between Week 0 and Week 28 ]
  To assess efficacy of 3 doses of S201086/GLPG1972 versus placebo on the bone area of the target knee using quantitative MRI of the medial femoral condyle surface.
• Change from baseline in bone area of the medial femoral condyle surface of the target knee by quantitative MRI. [ Time Frame: Between Week 0 and Week 52 ]
  To assess efficacy of 3 doses of S201086/GLPG1972 versus placebo on the bone area of the target knee using quantitative MRI of the medial femoral condyle surface.
• The change from baseline in Joint Space Width (JSW) of the target knee measured by X-Ray. [ Time Frame: Between Week 0 and Week 52. ]
  To assess efficacy of 3 doses of S201086/GLPG1972 versus placebo after 52 weeks of treatment on the target knee using X-ray.
• Pain: analgesic consumption throughout the study. [ Time Frame: Between Week 0 and Week 52. ]
  To assess efficacy of 3 doses of S201086/GLPG1972 versus placebo after 52 weeks of treatment on analgesic consumption.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Assess Efficacy and Safety of GLPG1972/S201086 in Participants With Knee Osteoarthritis
• Official Title: Efficacy and Safety of 3 Doses of S201086/GLPG1972 Administered Orally Once Daily in Patients With Knee Osteoarthritis. A 52-week International, Multi-regional, Multi-center, Randomized, Double-blind, Placebo-controlled, Dose-ranging Study
• Brief Summary: This study is a phase 2, 52-week international, multi-regional, multi-center, randomized, double-blind, placebo-controlled dose-ranging study for the treatment of osteoarthritis.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Osteoarthritis

Intervention

• Drug: GLPG1972
  Film-coated tablets of GLPG1972 for oral use.
• Drug: Placebo
  Film-coated tablets of matching placebo for oral use.

Study Arms

• Experimental: GLPG1972 75 mg
  Participants received 1 film-coated tablet of GLPG1972 75 mg and 3 GLPG1972 matching placebo tablets, orally once daily for 52 weeks.
  Interventions:

  • Drug: GLPG1972
  • Drug: Placebo
• Experimental: GLPG1972 150 mg
  Participants received 2 film-coated tablets of GLPG1972 75 mg (total dose 150 mg) and 2 GLPG1972 matching placebo tablets, orally once daily for 52 weeks.
  Interventions:

  • Drug: GLPG1972
  • Drug: Placebo
• Experimental: GLPG1972 300 mg
  Participants received 4 film-coated tablets of GLPG1972 75 mg (total dose 300 mg), orally once daily for 52 weeks.
  Intervention: Drug: GLPG1972
• Placebo Comparator: Placebo
  Participants received 4 film-coated tablets of GLPG1972 matching placebo, orally once daily for 52 weeks.
  Intervention: Drug: Placebo

• Publications *: Brebion F, Gosmini R, Deprez P, Varin M, Peixoto C, Alvey L, Jary H, Bienvenu N, Triballeau N, Blanque R, Cottereaux C, Christophe T, Vandervoort N, Mollat P, Touitou R, Leonard P, De Ceuninck F, Botez I, Monjardet A, van der Aar E, Amantini D. Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis. J Med Chem. 2021 Mar 25;64(6):2937-2952. doi: 10.1021/acs.jmedchem.0c02008. Epub 2021 Mar 15.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 20, 2021): 932
• Original Estimated Enrollment (submitted: July 20, 2018): 852
• Actual Study Completion Date: July 14, 2020
• Actual Primary Completion Date: July 14, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male participants or female participants of non-childbearing potential and not breastfeeding.
• Body weight > 40 kg, body mass index (BMI) < 40 kg/m^2.
• Diagnosed for knee osteoarthritis based on clinical and radiological criteria of the American College of Rheumatology.
• History of knee pain for at least 6 months and on the majority of days (> 50%) during the preceding month.
• Symptom severity defined by a pain ≥ 40 mm and ≤ 90 mm on visual analogue scale (VAS, 100 mm) at screening and inclusion visits.
• Documented need for symptomatic as needed-treatment for osteoarthritis (OA) in the target knee with systemic non-steroidal anti-inflammatory drugs (NSAIDs) and/or other analgesics

Exclusion Criteria:

• Severe clinical knee malalignment according to the investigator.
• Knee prosthesis already implanted (< 1 year) or not well-tolerated (contralateral side).
• Knee prosthesis already foreseen within the study period (whichever side).
• Hip prosthesis recently implanted (< 1 year) or foreseen within the study period (whichever side).
• Previous osteotomy on the inferior limbs (whichever side).
• Surgical operation on the target knee within the 12 months prior to the screening visit or planned during the study.
• Diagnostic arthroscopy of the target knee within the 6 months prior to the screening visit or planned during the study.
• Other pathologies affecting the target knee.
• Any contraindication to magnetic resonance imaging (MRI) including the inability to undergo a knee MRI exam because of inability to fit in the scanner or knee coil.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03595618
• Other Study ID Numbers: GLPG1972-CL-201; 2017-004581-10 ( EudraCT Number ); U1111-1205-0321 ( Other Identifier: Universal Trial Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Galapagos NV
• Original Responsible Party: Same as current
• Current Study Sponsor: Galapagos NV
• Original Study Sponsor: Same as current
• Collaborators: Institut de Recherches Internationales Servier

Investigators

• Study Director: Galapagos Study Director; Galapagos NV

• PRS Account: Galapagos NV
• Verification Date: July 2021