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    Summary
    EudraCT Number:2013-004940-48
    Sponsor's Protocol Code Number:2013-004940-48
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-10-03
    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 ConcernedSweden - MPA
    A.2EudraCT number2013-004940-48
    A.3Full title of the trial
    Denosumab For Treating Periprosthetic Osteolysis After Uncemented Total Hip Arthroplasty. A randomized, double-blind, placebo-controlled trial using volumetric computed tomography.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to see if a drug called Denosumab, affecting bone tissue and mineralization of the bone, will improve the outcome of Total Hip replacement surgery.
    A.4.1Sponsor's protocol code number2013-004940-48
    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 SponsorDanderyds Hospital, Department of Clinical Sciences, Division of Orthopaedics
    B.1.3.4CountrySweden
    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 supportAmgen
    B.4.2CountrySweden
    B.4.1Name of organisation providing supportALF
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDanderyds Hospital, Department of Clinical Sciences, Division of Orthopaedics
    B.5.2Functional name of contact pointOlof Sköldenberg
    B.5.3 Address:
    B.5.3.1Street AddressDanderyds Hospital
    B.5.3.2Town/ cityDanderyd
    B.5.3.3Post codeSE-182 88
    B.5.3.4CountrySweden
    B.5.4Telephone number+4670089 12 53
    B.5.6E-mailolof.skoldenberg@ki.se
    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
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    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 INNDenosumab
    D.3.9.1CAS number 615258-40-7
    D.3.9.3Other descriptive nameDENOSUMAB
    D.3.9.4EV Substance CodeSUB29173
    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 No
    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.IMP: 2
    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 Kalcipos®-D
    D.2.1.1.2Name of the Marketing Authorisation holderRecip
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCalcium Carbonate
    D.3.9.3Other descriptive nameCALCIUM CARBONATE
    D.3.9.4EV Substance CodeSUB13166MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.3
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCHOLECALCIFEROL
    D.3.9.3Other descriptive nameCHOLECALCIFEROL
    D.3.9.4EV Substance CodeSUB34314
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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 placeboSolution for injection in pre-filled syringe
    D.8.4Route of administration of the placeboSubcutaneous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with titanium press-fit acetabular components with polyethylene liners will be screened for osteolytic lesions. The patients had primary surgery at least 7 years before screening and all operated due to osteoarthritis of the hip. We expect that approximately 30% of screened patients will have an osteolytic lesion. These patients with screening-detected lesions as well as patients with previously known osteolytic lesions will be eligible for inclusion in the study.
    E.1.1.1Medical condition in easily understood language
    Patients with hip implants (THA) performed at least 7 years before inclusion with possible or known loosening of implant due to bone dissolution (osteolytic lesions).
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective is to study the efficacy of denosumab in reducing wear-induced osteolysis around uncemented acetabular implants used in THA.
    E.2.2Secondary objectives of the trial
    The change in volume of the osteolytic lesion over 2 years.
    Percentage change of the lesion over the study period.
    Hip-specific outcome scores at inclusion and 1, 2 and 3 years.
    Percent change in BMD in vertebrae L1-L4 to investigate if there is an overall increase in bone mass in these patients.
    Correlation between change in bone turnover markers and progression of osteolysis.
    Changes in Serum Concentrate values for RANKL and Osteoprogesterin, to determine how Serum level correlates with changes in Osteolytic Volume.
    Occurrence of AE´s.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age 40-85 years
    • Short Portable Mental Status Questionnaire (SPMSQ) also named Pfeiffertest ≥7 correct responses or alternatively ≤ 3 incorrect responses
    • Male and females
    • The primary THA performed at least 7 years before inclusion.
    • The primary THA performed due to osteoarthritis or congenital dysplasia of the hip.
    • Uncemented cup fixation
    • Baseline osteolytic lesion of at least 2 cm³ and at most 40 cm³ around an uncemented acetabular component with a polyethylene liner.
    • Participant is willing and able to follow study protocol and has provided informed consent prior to any study specific procedures.
    E.4Principal exclusion criteria
    • Women that are pregnant or women planning to become pregnant or planning to breastfeed
    • For women of childbearing potential (menopausal state -determined??): Subject refuses to use 1 highly effective method of contraception (contraceptive pill, intra uterine contraceptive device) for the duration of the study and for 5 months after the last dose of study medication.
    • For women of childbearing potential: Subject refrain from breastfeeding for the duration of the study and for 5 months after the last dose of study medication.
    • For males with a partner of childbearing potential: Subject refuses to use a condom for the duration of the study and for 5 months after the last dose of study medication.For males with a partner who is pregnant: Subject refuses to use a condom for the duration of the study and for 5 months after the last dose of study medication.
    • Women that are pregnant or breastfeeding or women planning to become pregnant or planning to breastfeed.
    • Pain in the operated hip (because the presence of hip pain in combination with an osteolytic lesion is an indication for revision surgery) as defined by a visual analog scale (VAS) score >3
    • Previous revision surgery of the hip i.e. exchange of any inplant after the primary surgery
    • Inflammatory arthritis
    • Previous participation in clinical trials with denosumab or administration of commercial denosumab (Prolia™ or Xgeva™)
    • Currently enrolled in or has not yet completed at least 1 month since ending other investigational device or drug trial(s), or subject is receiving other investigational agent(s).
    • Treatment with any intravenous bisphosphonate, fluoride (except for dental treatment) or strontium ranelate within 5 years prior to inclusion.
    • Treatment with any oral bisphosphonate within 1 year prior to inclusion.
    • Treatment with cortisol or cytostatic drugs within 6 months prior to inclusion.
    • Administration of any of the following treatments 3 months prior to screening:
    Anabolic steroids or testosterone
    Glucocorticosteroids (≥ 5 mg prednisone equivalent per day for more than 10 days or a total cumulative dose of ≥ 50 mg)
    Calcitonin
    Calcitriol or vitamin D derivatives [vitamin D contained in supplements or multivitamins is allowed]
    Other bone active drugs including anti-convulsives (except benzodiazepines, gabapentin and pregabalin) and heparin
    Chronic systemic ketoconazole, ACTH (adrenocorticotrophic hormone), cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, gonadotropin-releasing hormone agonists.
    Androgen deprivation therapy
    • Hypocalcaemia.
    • Bone metabolic disorders (such as OI, PHPT, Paget)
    • History of osteonecrosis of the jaw and/or recent (within prior 6 months) tooth extraction or dental surgery; or planned invasive dental proceedures during the study
    • Serum 25-OH D <15 ng/ml
    • Significant malabsorption including Celiac Disease, Short Bowel Syndrome, Crohn’s Disease, Previous Gastric Bypass.
    • Active cancer and/or malignancy in last 5 years (except cervical carcinoma in situ or basal cell carcinoma)
    • History of solid organ or bone marrow transplant.
    • Hypersensitivity to any components of study drug.
    • Intolerance to calcium supplements.
    • Pregnancy and/or currently lactating.
    • Significantly impaired renal function as determined by a derived glomerular filtration rate (GFR) using Cockcroft Gault formula of  30 mL/min/1.73 m2
    • Elevated transaminases ≥ 2.0 x upper limit of normal (ULN); Elevated total bilirubin (TBL) > 1.5 x ULN.
    • Any condition or illness (acute, chronic, or history), which in the opinion of the Investigator might interfere with the evaluation of efficacy and safety during the study or may otherwise compromise the safety of the subject.
    E.5 End points
    E.5.1Primary end point(s)
    The change in volume of the osteolytic lesion over 3 years (measured with 3D-CT in cm³):
    Efficacy(3 years) = Volume(3 years) - Volume(baseline).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Screening, 3 years
    E.5.2Secondary end point(s)
    The change in volume of the osteolytic lesion over 2 years (measured with 3D-CT in cm³)
    Efficacy (2 years) = Volume (2years ) - Volume (baseline).

    Percentage change of the lesion over the study period.(14)

    Hip-specific outcome scores (Harris hip score(31)[HHS], WOMAC (32)), Pain Numerical Rating Scale (PNRS), Activity Scores (UCLA and Johnston) and Health-related quality of life (EQ-5D)(33) at inclusion and 1, 2 and 3 years.

    Percent change from baseline in BMD in vertebrae L1-L4 and measured with dual-energy x-ray absorptiometry (DXA) at 3 years to investigate if there is an overall increase in bone mass in these patients. Previous studies on denosumab have focused on patients with osteoporosis or other metabolic bone disease and it is to be expected that the patients in this trial will have a normal bone mass.

    Correlation between change in bone turnover markers 6 months after first injection and progression of osteolysis . Serum C-terminal telopeptide of type I collagen (SCTx)(34) and procollagen type 1 amino-terminal propeptide (P1NP)(35) will be controlled through blood samples at inclusion and every 6 months (before each injection).

    Exploratory Endpoints.
    Changes in Serum Concentrate values for RANKL and Osteoprogesterin, to determine how Serum level correlates with changes in Osteolytic Volume

    Occurrence of AE´s
    E.5.2.1Timepoint(s) of evaluation of this end point
    Screening/randomization, 6 months, 1 year, 1.5 years, 2 years. 2.5 years and 3 years.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    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 trial2
    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.8.5The 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 No
    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 years6
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state110
    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)
    After study termination the treatment will continue according to the local clinical routines.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-11-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-05
    P. End of Trial
    P.End of Trial StatusCompleted
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