DISKO: Effect of denosumab on pain and bone marrow lesions in knee osteoarthritis
| ISRCTN | ISRCTN96920058 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN96920058 |
| EudraCT/CTIS number | 2016-000754-35 |
| IRAS number | 191262 |
| Secondary identifying numbers | CPMS 34642, IRAS 191262 |
- Submission date
- 31/05/2017
- Registration date
- 01/06/2017
- Last edited
- 22/08/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Musculoskeletal Diseases
Plain English Summary
Background and study aims
Knee osteoarthritis (OA) occurs when the protective cartilage on the end of bones wears away. The bones in the knee then rub against one another, causing stiffness, pain and a reduction in the range of movement. Knee OA is the most common cause of knee pain in older adults. Despite this, there are no effective treatments which reduce knee pain and the rate at which the disease progresses. Current treatments are limited due to their side effects and the fact that many are not particularly effective. Recent research, however, suggests that treatments which prevent bone loss may be effective at reducing pain and joint damage in people with knee osteoarthritis. Denosumab is a medication that is used to prevent bone loss and could be helpful to relieve pain for those with knee OA. The aim of this study is to determine whether a one off administration of denosumab, and given as an injection under the skin, is effective at relieving pain in people with painful knee OA and reducing structural damage at the knee.
Who can participate?
Adults aged 50 years and older who have osteoarthritis of the knee
What does the study involve?
Participants undergo an x-ray, blood test and MRI prior to joining the study. They are then randomly allocated to one of two groups. Those in the first group receive a single injection (under the skin) of 60 mg of denosumab. Those in the second group receive a placebo (dummy) injection. Both groups receive a questionnaire to assess their pain and arthritis symptoms. They are instructed to take calcium and vitamin D supplements. Participants attend a follow up appointment three and six months after they receive the injection. One week before each follow up appointment they are asked to wear an activity monitor for seven days. At the three month appointment, participants repeat the questionnaires and undergo a blood test to evaluate their calcium levels. At the six month follow up appointment, participants receive another MRI to assess the changes in their bone marrow lesions and repeat the questionnaire again to see if there has been changes in their knee OA symptoms and pain levels.
What are the possible benefits and risks of participating?
There are no direct benefits with participating. Denosumab has been widely used by physicians for over five years, however, as with any medication there are always potential risks which should be reviewed with the study doctor or GP. There is a small risk of radiation exposure associated with X-Ray’s. Participants may experience claustrophobia (anxiety when in tight spaces) or feel uncomfortable while undergoing the MRI scan. There is a risk of discomfort when providing blood tests.
Where is the study run from?
Salford Royal Hospital (UK)
When is the study starting and how long is it expected to run for?
January 2016 to October 2020
Who is funding the study?
Arthritis UK (UK)
Who is the main contact?
Dr Gillian Armitt
gillian.armitt@manchester.ac.uk
Contact information
Public
Research in OsteoArthritis Manchester (ROAM)
Centre for Musculoskeletal Research
Division of Musculoskeletal & Dermatological Sciences
School of Biological Sciences
Faculty of Biology, Medicine and Health
The University of Manchester
Stopford Building
Oxford Road
Manchester
M13 9PT
United Kingdom
| Phone | +44 (0)161 306 0545/0547 |
|---|---|
| gillian.armitt@manchester.ac.uk |
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised parallel trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | No participant information sheet available |
| Scientific title | The effect of Denosumab on pain and bone marrow lesions In Symptomatic Knee Osteoarthritis: a randomised double blind placebo controlled clinical trial |
| Study acronym | DISKO |
| Study hypothesis | The aim of this study is to determine whether a one off administration of a drug treatment which prevents bone loss called ‘denosumab’, and given as an injection under the skin, is effective at relieving pain in people with painful knee OA and reducing structural damage at the knee. |
| Ethics approval(s) | North West - Greater Manchester South Research Ethics Committee, 22/05/2017, ref: 17/NW/0262 |
| Condition | Osteoarthritis of the knee |
| Intervention | Prior to the study, potential participants are screened for eligibility with a knee x-ray, blood test, and a MRI scan to assess for Bone Marrow Lesions (BML). Those who meet the eligibility criteria, including the presence of BML on MRI are accepted to the study. Participants are randomised (50:50) to receiving either a single injection (under the skin) of 60 mg denosumab or to have a matched placebo and fill a questionnaire about their osteoarthritis. Participants receive calcium and vitamin D supplements. Participants have two follow up appointments three and six months after the initial injection. One week before each appointment participants are also be asked to wear an activity monitor for seven days. At the three month follow up participants repeat the questionnaires to assess their pain and arthritis symptoms as well as undergo a blood test to evaluate their calcium levels. At the six month follow up participants have another MRI scan to assess their change in bone marrow lesions and they also repeating the questionnaire. |
| Intervention type | Other |
| Primary outcome measure | Total area of bone marrow lesions (assessed on MRI) at six months. |
| Secondary outcome measures | 1. Knee pain using an 11 point (0–10) numerical rating scale (NRS) of knee pain intensity, at baseline, three, and six months. The change in knee pain using a NRS scale is the primary outcome recommended by IMMPACT (http://immpact.org/) 2. Knee pain on nominated activity using an 11 point (0-10) numerical rating scale (NRSNA) at three and six months 3. Knee symptoms assessed using KOOS at three and six months 4. Quality of life assessed using EuroQOL & SF12 at three and six months 5. Adverse events are assessed from data collected at each study visit 6. Bone marrow lesions (BML) volume measured on MRI at baseline and six months |
| Overall study start date | 04/01/2016 |
| Overall study end date | 30/10/2020 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | Planned Sample Size: 167; UK Sample Size: 167 |
| Total final enrolment | 58 |
| Participant inclusion criteria | Current participant inclusion criteria as of 02/10/2019: 1. Age 40 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 3 out of 10 on the primary symptom outcome of the trial, knee pain on a numerical rating scale (NRS Last week ≥3) 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 Previous participant 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 10 on the primary symptom outcome of the trial, knee pain on a numerical rating scale (NRS Last week ≥4) 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 |
| Participant exclusion criteria | Current participant exclusion criteria as of 02/10/2019: 1. History of septic arthritis affecting the index knee 2. History of inflammatory arthritis 3. Current treatment for gout and/or acute attack of gout within the previous 5 years 4. GFR < 35 ml/min 5. Vitamin D level of < 50 nmol/l 6. Abnormal liver function (ALT or AST > twice upper limit of normal) or elevated total bilirubin > 1.5 x ULN 7. 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 8. History of malignancy in the past 5 years (other than basal cell carcinoma) 9. History of any solid organ or bone marrow transplant 10. History of alcohol abuse within previous 12 months 11. Known hypersensitivity to Latex 12. Hereditary problems of fructose intolerance 13. Non-healed dental / oral surgery 14. History of cellulitis of the lower limb within the last 5 years, osteonecrosis of the jaw, osteonecrosis of the external auditory meatus or atypical femoral fracture 15. Unhealed open soft tissue lesions in the mouth 16. History of invasive dental surgery in previous 6 months and/or invasive dental work planned in the next 6 months 17. Current anorexia nervosa, suspected bulimia (by history or physical examination) or obvious malnutrition 18. Active inflammatory bowel disease or current or recent malabsorption syndrome. 19. Hypo or hyperparathyroidism 20. Hypocalcemia (Calcium < LLN) / hypercalcemia (Ca > Upper Limit of Normal [ULN]) 21. Osteoporosis on bone active therapy 22. Current or recent Osteomalacia (within the last 5 years) or other bone diseases which may affect bone metabolism (osteopetrosis / osteogenesis imperfecta) 23. Suspected knee fracture 24. Intra-articular therapy in the knee within the previous 3 months 25. Prior antiresorptive therapy with bisphosphonates in the last year (oral therapy) or 3 years (IV therapy) 26. Prior treatment in the last year with strontium ranelate / HRT / raloxifene / testosterone 27. Previous knee surgery (including cartilage surgery) or arthroscopy within 6 months on the affected knee 28. Planned knee or hip surgery in the next 6 months 29. Currently having physiotherapy for knee OA 30. Women of childbearing potential currently pregnant or planning pregnancy or breast feeding 31. Women of childbearing potential and refusal to use at least one highly effective form of contraception (methods that can achieve a failure rate of less than 1% per year when used consistently and correctly) and to continue until 5 months following intervention. 32. Concurrent life threatening illness or any other condition that in the opinion of the investigator would compromise participants safety or data integrity 33. 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 34. 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) 35. 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 36. Unable to understand or retain the information provided regarding the trial procedures 37. Known hypersensitivity to denosumab or any ingredients of Prolia Previous exclusion criteria as of 13/08/2018: 1. History of septic arthritis affecting the index knee 2. History of inflammatory arthritis 3. Current treatment for gout and/or acute attack of gout within the previous 5 years 4. GFR < 35 ml/min 5. Vitamin D level of < 50 nmol/l 6. Abnormal liver function (ALT or AST > twice upper limit of normal) or elevated total bilirubin > 1.5 x ULN 7. 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 8. History of malignancy in the past 5 years (other than basal cell carcinoma) 9. History of any solid organ or bone marrow transplant 10. History of alcohol abuse within previous 12 months 11. Known hypersensitivity to Latex 12. Hereditary problems of fructose intolerance 13. Non-healed dental / oral surgery 14. History of cellulitis of the lower limb within the last 5 years, osteonecrosis of the jaw, osteonecrosis of the external auditory meatus or atypical femoral fracture 15. Unhealed open soft tissue lesions in the mouth 16. History of invasive dental surgery in previous 6 months 17. Invasive dental work planned in the next 6 months 18. Current anorexia nervosa, suspected bulimia (by history or physical examination) or obvious malnutrition 19. Active inflammatory bowel disease or current or recent malabsorption syndrome. 20. Hypo or hyperparathyroidism 21. Hypocalcemia (Calcium < LLN) / hypercalcemia (Ca > Upper Limit of Normal [ULN]) 22. Osteoporosis on bone active therapy 23. Current or recent Osteomalacia (within the last 5 years) 24. Other bone diseases which may affect bone metabolism (osteopetrosis / osteogenesis imperfecta) 25. Intra-articular therapy in the knee within the previous 3 months 26. Prior antiresorptive therapy with bisphosphonates in the last year (oral therapy) or 3 years (IV therapy) 27. Prior treatment in the last year with strontium ranelate / HRT / raloxifene / testosterone 28. Previous knee surgery (including cartilage surgery) or arthroscopy within 6 months on the affected knee 29. Planned knee or hip surgery in the next 6 months 30. Currently having physiotherapy for knee OA 31. Women of childbearing potential currently pregnant or planning pregnancy or breastfeeding 32. Women of childbearing potential and refusal to use at least one highly effective form of contraception (methods that can achieve a failure rate of less than 1% per year when used consistently and correctly) and to continue until 5 months following intervention. 33. Concurrent life threatening illness or any other condition that in the opinion of the investigator would compromise participants safety or data integrity 34. 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 35. 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) 36. 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. 37. Unable to take in, understand or retain the information provided regarding the trial procedures. 38. Known hypersensitivity to denosumab or any ingredients of Prolia Previous exclusion criteria from 04/05/2018 to 13/08/2018: 1. History of septic arthritis, inflammatory arthritis or gout 2. Vitamin D level of <50 nmol/l 3. Abnormal liver function (ALT or AST >2x upper limit of normal) or elevated total bilirubin >1.5x 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. Unhealed open soft tissue lesions in the mouth 13. History of invasive dental surgery in previous 6 months 14. Invasive dental work planned in the next 6 months 15. Current anorexia nervosa, suspected bulimia (by history or physical examination) or obvious malnutrition 16. Current or recent (within 1 year of enrolment) inflammatory bowel disease or malabsorption syndrome. 17. Hypo or hyperparathyroidism 18. Hypocalcemia (Calcium < LLN) / hypercalcemia (Ca > Upper Limit of Normal [ULN]) 19. Osteoporosis on bone active therapy 20. Osteomalacia 21. Other bone diseases which may affect bone metabolism (osteopetrosis / osteogenesis imperfecta) 22. Known intolerance to calcium supplements 23. Intra-articular therapy in the knee within the previous 3 months 24. Prior antiresorptive therapy with bisphosphonates in the last year (oral therapy) or 3 years (IV therapy) 25. Prior treatment in the last year with strontium ranelate / HRT / raloxifene / testosterone 26. Previous knee surgery (including cartilage surgery) or arthroscopy within 6 months on the affected knee 27. Planned knee or hip surgery in the next 6 months 28. Currently having physiotherapy for knee OA 29. Women of childbearing potential currently pregnant or planning pregnancy or breast feeding 30. Women of childbearing potential and refusal to use at least one highly effective form of contraception (methods that can achieve a failure rate of less than 1% per year when used consistently and correctly) and to continue until 5 months following intervention. 31. Concurrent life threatening illness or any other condition that in the opinion of the investigator would compromise participants safety or data integrity 32. 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 33. 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) 34. 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. 35. Unable to take in, understand or retain the information provided regarding the trial procedures. 36. Known hypersensitivity to denosumab or any ingredients of Prolia Original 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 |
| Recruitment start date | 01/07/2017 |
| Recruitment end date | 26/02/2020 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Stott Lane
Salford
M6 8HD
United Kingdom
Sponsor information
University/education
Oxford Road
Manchester
M13 9PL
England
United Kingdom
| Phone | +44 (0)161 275 2725 |
|---|---|
| Clinicaltrials@manchester.ac.uk | |
"ROR" |
https://ror.org/027m9bs27 |
Funders
Funder type
Charity
Private sector organisation / Other non-profit organizations
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/12/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal. |
| IPD sharing plan | Anonymised patient-level data may be shared by application to the Principal Investigator. This would be subject to the proposed research being in accordance with arrangements for data sharing in the Participant Information Sheet and Consent Form; and any necessary data sharing contracts and ethical approvals for the research being in place. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Basic results | version 1.0 | 16/12/2021 | 21/12/2021 | No | No |
| Protocol file | version 2.7 | 16/05/2019 | 22/08/2022 | No | No |
| HRA research summary | 28/06/2023 | No | No |
Additional files
Editorial Notes
22/08/2022: Protocol file uploaded.
21/12/2021: The following changes have been made:
1. The basic results of this trial have been uploaded as an additional file.
2. The IRAS number has been added.
3. The Individual participant data (IPD) sharing statement has been added and the IPD sharing summary has been changed from "Data sharing statement to be made available at a later date" to "Available on request".
21/10/2021: The following changes were made to the trial record:
1. The study contact has been updated and the plain English summary has been updated accordingly.
2. The intention to publish date was changed from 01/10/2021 to 31/12/2022.
01/12/2020: The following changes were made to the trial record:
1. The overall trial end date was changed from 01/12/2020 to 30/10/2020.
2. The intention to publish date was changed from 31/08/2020 to 01/10/2021.
3. The total final enrolment was added.
16/04/2020: The recruitment end date was changed from 01/12/2020 to 26/02/2020.
21/01/2020: The condition has been changed from "Specialty: Musculoskeletal disorders, Primary sub-specialty: Non-inflammatory Joint Disorders; UKCRC code/ Disease: Musculoskeletal/ Other osteopathies" to "Osteoarthritis of the knee" following a request from the NIHR.
02/10/2019: The following changes were made to the trial record:
1. The recruitment end date was changed from 28/02/2019 to 01/12/2020.
2. The overall end date was changed from 31/08/2019 to 01/12/2020.
3. The inclusion criteria were changed.
4. The exclusion criteria were changed.
13/08/2018: The study contact and exclusion criteria were updated.
04/05/2018: The participant exclusion criteria have been changed.
23/10/2017: Internal review.
