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    Summary
    EudraCT Number:2016-000754-35
    Sponsor's Protocol Code Number:R118528
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-05-08
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2016-000754-35
    A.3Full title of the trial
    The effect of Denosumab on Pain and bone Marrow Lesions in symptomatic Knee Osteo-arthritis: A Randomised Double Blind Placebo controlled Clinical Trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The Effect of Denosumab on Pain and Bone Marrow Lesions in Symptomatic Knee Osteo-arthritis : A Randomised Double Blind Placebo Controlled Clinical Trial
    A.3.2Name or abbreviated title of the trial where available
    DISKO: Effect of Denosumab on pain and BMLs in knee osteoarthritis
    A.4.1Sponsor's protocol code numberR118528
    A.5.4Other Identifiers
    Name:AMGEN referenceNumber:Prolia ISS 20149112
    Name:MAHSC-CTU referenceNumber:15_CTU_026
    Name:Sponsor Trial Reference IDNumber:R118528
    Name:ARUK funding referenceNumber:ARUK 20829
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorThe University of Manchester
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportArthritis Research UK
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportAMGEN
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThe University of Manchester
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street Address2.518 Stopford Building
    B.5.3.2Town/ cityManchester
    B.5.3.3Post codeM13 9PT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01613060549
    B.5.6E-mailhelen.williams@manchester.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Prolia
    D.2.1.1.2Name of the Marketing Authorisation holderAMGEN Europe B.V
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameProlia
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDensoumab
    D.3.9.1CAS number 615258-40-7
    D.3.9.2Current sponsor codeR118528
    D.3.9.3Other descriptive nameProlia
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSuspension for injection in pre-filled syringe
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Knee osteoarthritis
    E.1.1.1Medical condition in easily understood language
    Knee joint damage due to wear and tear
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10023476
    E.1.2Term Knee osteoarthritis
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary 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
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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
    E.5.1.1Timepoint(s) of evaluation of this end point
    Total BML area, assessed on magnetic resonance imaging (MRI) at 6 months
    E.5.2Secondary 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.
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 67
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state167
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 167
    F.4.2.2In the whole clinical trial 167
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    There are no arrangements for the continued provision of Denosumab to participants after they complete participation in the DISKO study. Should the results of the trial be positive however, the Research team will pursue additional funding with pharmaceutical industry and grant support to look at implementation into clinical practice.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-07-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-10-30
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