E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prosthesis-related osteolysis after total hip arthroplasty |
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E.1.1.1 | Medical condition in easily understood language |
A patient with a hip joint replacement that becomes loose and unstable and is not caused by infection.
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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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057128 |
E.1.2 | Term | Revision of hip arthroplasty |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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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 |
The primary objective is to find out whether denosumab treatment, compared to the placebo,reduces the number of osteoclasts (bone resorbing cells) in the bone around the area of the hip replacement. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives will be to compare the effect of denosumab to placebo on: [1]. Bone turnover markers measured in the blood 8 weeks after administration of the medications. [2]. Measurements of the bone tissue surfaces around the hip replacement 8 weeks after administration of the medications. [3]. The survival and growth of bone cells in the bone tissue around the hip replacement |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Participants must be men or women over 30 years of age undergoing revision THA surgery for periprosthetic osteolysis / aseptic loosening affecting the pelvis and / or femur. 2. Participants must also be willing and able to give fully informed consent. 3. Participants must have osteolysis / aseptic loosening affecting fully cementless, hybrid, or fully cemented THA prosthesis |
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E.4 | Principal exclusion criteria |
The following exclusion criteria will apply: 1. Known prosthesis infection 2. Pregnancy / Breast feeding 3. Oral bisphosphonate therapy (current use, previous use within the last 12 months, previous 3 or more years cumulative use) 4. Administration of intravenous bisphosphonate, fluoride or strontium within the last 5 years 5. Participation in ongoing or previous denosumab clinical trials 6. Administration of any of the following treatments within the last 12 months 7. PTH or PTH derivatives, eg, teriparatide 8. anabolic steroids or testosterone 9. glucocorticosteroids (> 5 mg prednisone equivalent per day for more than 10 days) 10. systemic hormone replacement therapy 11. selective estrogen receptor modulators (SERMs), eg, raloxifene tibolone, calcitonin or calcitriol 12. Any subject in whom denosumab is contra-indicated according to the local SmPC of denosumab (SC 60 mg every 6 months in UK) 13. Current hypocalcemia (albumin adjusted serum calcium below 2.13 mmol/L) 14. History of rheumatoid arthritis 15. History of Paget’s disease 16. Malignancy (except basal cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years 17. Renal insufficiency assessed by eGFR <30 18. Known sensitivity to mammalian cell derived drug products 19. Any organic or psychiatric disorder, or laboratory abnormality which, in the opinion of the Investigator, will prevent the subject from completing the study or interfere with the interpretation of the study results 20. Any disorder that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent and/or comply with study procedures 21. Evidence of alcohol or substance-abuse within the last 12 months that the Investigator believes would interfere with understanding or completing the study 22. Subject is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug trial(s), or subject is receiving other investigational agent(s).
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E.5 End points |
E.5.1 | Primary end point(s) |
Absolute difference between study groups in osteoclast number per millimetre at the osteolysis membrane-bone interface, measured by cell counting in histological sections between the denosumab and placebo groups, 8 weeks after administration of the IMP |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary outcome measure (difference in osteoclast number) will be made at 8 weeks after administration of the IMP
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E.5.2 | Secondary end point(s) |
Tissue level measurements of osteoclast, macrophage and fibroblast proliferation and apoptosis rates in denosumab versus placebo treated subjects is a secondary outcome measure in this study that will provide useful mechanistic information for differences in cell populations between the study groups. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary outcome measures will be made at 8 weeks after administration of the IMP
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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 | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Proof of Concept/Exploratory |
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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 | No |
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 | 2 |
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.8.5 | 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 | 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
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To avoid drifts or shifts in measurements, laboratory analysis will be completed all together once all study visits have been completed and all samples have been collected. To ensure that all sample analysis is completed satisfactorily before end of study is declared, we will consider the trial complete when all subjects have completed visit 5, all analyses completed, all data has been entered, checked and cleaned and the database locked. |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |