The effect of Denosumab on Pain and bone Marrow Lesions in symptomatic Knee Osteo-arthritis: A Randomised Double Blind Placebo controlled Clinical Trial

INTERVENTION: Trade Name: Prolia Product Name: Prolia Pharmaceutical Form: Solution for injection INN or Proposed INN: Densoumab CAS Number: 615258‐40‐7 Current Sponsor code: R118528 Other descriptive name: Prolia Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 60‐ Pharmaceutical form of the placebo: Suspension for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use CONDITION: Knee osteoarthritis ; MedDRA version: 20.0 Level: LLT Classification code 10023476 Term: Knee osteoarthritis System Organ Class: 100000004859 Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] PRIMARY OUTCOME: Main Objective: To determine the effect of a single subcutaneous injection of denosumab (60mg) on the total bone marrow lesion area (bone bruising) in subjects with symptomatic knee osteoarthritis Primary end point(s): Primary objective ; To determine the effect of a single denosumab 60mg subcutaneous (SC) dose on the total bone marrow lesion (BML) area in subjects with symptomatic knee osteoarthritis (OA) ; ; Primary Outcome; Total BML area, assessed on magnetic resonance imaging (MRI) at baseline and 6 months; Secondary Objective: To determine the effect of a single denosumab 60mg subcutaneous (SC) dose on, ; i) the reduction in intensity of knee pain and knee symptoms after 3 and 6 months, ii) change in quality of life, iii) change in bone marrow lesion volume, in subjects with symptomatic knee osteoarthritis (OA) ; ; To determine whether there is any correlation between the reduction in knee pain and change in BMLs. ; ; To determine safety of therapy with denosumab Timepoint(s) of evaluation of this end point: Total BML area, assessed on magnetic resonance imaging (MRI) at 6 months SECONDARY OUTCOME: Secondary end point(s): 1. Change in knee pain using an 11 point (0–10) numerical rating scale (NRS Last week) of knee pain intensity, at 3 and 6 months. The change in knee pain using a NRS scale is the primary outcome recommended by IMMPACT (http://immpact.org/). ; ; 2. Change in knee pain on nominated activity using an 11 point (0‐10) numerical rating scale (NRSNA) at 3 and 6 months.; ; 3. Change in knee symptoms assessed using KOOS (Roos,1998) at 3 and 6 months (Roos,1998).; ; 4. Change in quality of life assessed using EuroQOL & SF12. We propose to assess the secondary outcomes at both 3 and 6 months.; ; 5. Adverse events; ; 6. BML volume measured on MRI. ; Timepoint(s) of evaluation of this end point: Records of pain intensity, QoL and BML volume change will be analysed from data collected at 3 and 6 months for all patients. INCLUSION CRITERIA: 1. Age 50 years and over. 2. Ambulatory (not wheel chair bound), and able and willing to comply with the intervention and follow up. 3. Significant knee pain (have at least a score of 4 out of 11 on the primary symptom outcome of the trial, knee pain on a numerical rating scale (NRS Last week)) 4. Evidence of significant OA on, x‐ray – Kellgren Lawrence grade 2 or 3. Participants can have Kellgren and Lawrence grade 2 or 3 in any knee compartment. 5. Evidence of BMLs in index knee on magnetic resonance scanning (MRI) 6. Written informed consent For those with bilateral symptomatic knee OA, we will select their more symptomatic knee for our primary outcome and will obtain the MRI's on this knee. If knees are equally symptomatic, we will study the one with the more severe radiographic changes (more likely to have BML's) and if both symptoms and radiographic changes are equivalent, we will choose the dominant knee. Are the trial sub