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 |
Knee joint damage due to wear and tear |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10023476 |
E.1.2 | Term | Knee osteoarthritis |
E.1.2 | System Organ Class | 100000004859 |
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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 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 |
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E.2.2 | Secondary objectives of the trial |
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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
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E.4 | Principal exclusion criteria |
1. History of septic arthritis, inflammatory arthritis or gout 2. Vitamin D level of < 50 nmol/l 3. Abnormal liver function (ALT or AST > twice upper limit of normal) or elevated total bilirubin > 1.5 x ULN 4. Potential participants with a positive Hepatitis B surface antigen (HBsAg) or hepatitis C test result or a history of immune-deficiency diseases, including a positive HIV test result 5. History of malignancy in the past 5 years (other than basal cell carcinoma) 6. History of any solid organ or bone marrow transplant 7. History of alcohol abuse within previous 12 months 8. Known hypersensitivity to Latex 9. Hereditary problems of fructose intolerance 10. Non-healed dental / oral surgery 11. History of cellulitis of the lower limb, osteonecrosis of the jaw or atypical femoral fractures 12. History of invasive dental surgery in previous 6 months 13. Invasive dental work planned in the 6 months 14. Current anorexia nervosa, suspected bulimia (by history or physical examination) or obvious malnutrition 15. Current or recent (within 1 year of enrolment) inflammatory bowel disease or malabsorption syndrome. 16. Hypo or hyperparathyroidism 17. Hypocalcemia (Calcium < LLN) / hypercalcemia (Ca > Upper Limit of Normal [ULN]) 18. Osteoporosis on bone active therapy 19. Osteomalacia 20. Other bone diseases which may affect bone metabolism (osteopetrosis / osteogenesis imperfecta) 21. Known intolerance to calcium supplements 22. Intra-articular therapy in the knee within the previous 3 months 23. Prior antiresorptive therapy with bisphosphonates in the last year (oral therapy) or 3 years (IV therapy) 24. Prior treatment in the last year with strontium ranelate / HRT / raloxifene / testosterone 25. Previous knee surgery (including cartilage surgery) or arthroscopy within 6 months on the affected knee 26. Planned knee or hip surgery in the next 6 months 27. Currently having physiotherapy for knee OA 28. Women of childbearing potential currently pregnant or planning pregnancy or breast feeding 29. Women of childbearing potential and refusal to use 2 highly effective forms of contraception and to continue until 5 months following intervention 30. Concurrent life threatening illness or any other condition that in the opinion of the investigator would compromise participants safety or data integrity 31. Contraindication to MRI such as implants which prohibit safe use of MRI scan including cochlear implants / metal objects in the body including certain joint prosthesis, cardiac or neural pacemakers, hydrocephalus shunts, or certain types of intrauterine-device. Also trial knee circumference must not be >55cm or weight >125kg as these exceed the maximum MRI limits 32. Currently enrolled in or has not yet completed at least 1 month since ending other investigational device or drug trial(s), or potential participant is receiving other investigational agent(s) 33. Pain from sites outside the knee that are significantly more troublesome to the potential participant than knee pain and which significantly interferes with the ability of the potential participant to assess their knee pain. 34. Unable to take in, understand or retain the information provided regarding the trial procedures.
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E.5 End points |
E.5.1 | 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
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Total BML area, assessed on magnetic resonance imaging (MRI) at 6 months |
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E.5.2 | 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.
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E.5.2.1 | 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. |
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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 | Yes |
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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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) | No |
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 | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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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 | 6 |
E.8.9.1 | In the Member State concerned days | 31 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 31 |