Effect of Denosumab on Inflammatory Osteolytic Lesion Activity in Total Hip Arthroplasty

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2012 by Sheffield Teaching Hospitals NHS Foundation Trust
Sponsor:
Collaborators:
Amgen
University of Sheffield
Information provided by (Responsible Party):
Sheffield Teaching Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier:
NCT01358669
First received: May 11, 2011
Last updated: December 14, 2012
Last verified: December 2012
  Purpose

Although hip replacement surgery is a successful way of dealing with the pain and immobility caused by hip arthritis, 10% of the hip replacements carried out in the UK fail within 10 years. The main reason for this is the development periprosthetic osteolysis, that is, loss of bone around the site of the hip replacement. The osteolysis is thought to be due to the small particles of debris worn from the surfaces of the hip implant. These particles cause a reaction in the blood cells around the joint which in turn affects bone cells and leads to a loss of bone around the implant. The joint implant will then eventually become loose and unstable, a condition known as aseptic loosening. At present the only way to treat aseptic loosening is to have another operation to secure the hip joint, known as revision surgery. Revision surgery is not always successful and exposes the patient to the risk of major surgery.

In this study we explore the potential for giving a medication (denosumab) that may prevent the loss of bone around the hip replacement implant. We will recruit patients who have been listed for revision surgery. One group of patients will be given a single dose of denosumab; another group will be given a placebo (dummy drug). At the time of the revision surgery a small sample of the bone from around the hip replacement will be taken and examined under the microscope. Comparisons will be made between the patients having the denosumab and those having placebo to find out whether the denosumab is having a beneficial effect on the bone surfaces. If successful, this study will lead to further studies to develop the use of denosumab to prevent aseptic loosening.


Condition Intervention Phase
Revision Surgery of Total Hip Arthroplasty
Drug: Denosumab
Other: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Effect of Denosumab on Inflammatory Osteolytic Lesion Activity in Total Hip

Resource links provided by NLM:


Further study details as provided by Sheffield Teaching Hospitals NHS Foundation Trust:

Primary Outcome Measures:
  • Osteoclast number [ Time Frame: 8 weeks after administration ] [ Designated as safety issue: No ]
    Absolute difference between study groups in osteoclast number per millimetre at the osteolysis membranebone interface, measured by cell counting in histological sections between the denosumab and placebo groups, 8 weeks after administration of the IMP


Secondary Outcome Measures:
  • Change in serum or urine levels of βCTXI, NTXI/Cr, TRAcP5b, CTXMMP, PINP, OPG, RANKL [ Time Frame: 8 weeks after administration of the IMP ] [ Designated as safety issue: No ]
    Difference between the denosumab and placebo groups in mean absolute change in serum or urine levels of βCTXI, NTXI/Cr, TRAcP5b, CTXMMP, PINP, OPG, RANKL, 8 weeks after administration of the IMP

  • Difference between the denosumab and placebo groups in mean eroded, quiescent, and osteoblast surfaces at the membrane bone interface [ Time Frame: 8 weeks after administration of the IMP ] [ Designated as safety issue: No ]
    Difference between the denosumab and placebo groups in mean eroded, quiescent, and osteoblast surfaces at the membrane bone interface measured using image analysis software, 8 weeks after administration of the IMP (Bioquant Image Analysis Corp, Nashville, TN, USA)

  • Difference between the denosumab and placebo groups in ratio of viable to apoptotic osteoclast, macrophage fibroblast, and osteoblasts by TUNEL staining and relative number of cells staining positive for apoptosis markers [ Time Frame: 8 weeks after administration of the IMP ] [ Designated as safety issue: No ]
    Difference between the denosumab and placebo groups in ratio of viable to apoptotic osteoclast, macrophage fibroblast, and osteoblasts by TUNEL staining and relative number of cells staining positive for apoptosis markers, including but not limited to, Caspase 8, 9, and 3, and proliferation marker Ki67 8 weeks after administration of the IMP


Estimated Enrollment: 30
Study Start Date: January 2012
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Denosumab
In this study we explore the potential for giving a medication (denosumab) that may prevent the loss of bone around the hip replacement implant
Drug: Denosumab
60mg denosumab by injection as a single dose
Other Name: Prolia
Placebo Comparator: Placebo
Placebo
Other: Placebo
Placebo by injection as a single dose

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   30 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.
  • Participants must also be willing and able to give fully informed consent.
  • Participants must have osteolysis / aseptic loosening affecting fully cementless, hybrid, or fully cemented THA prosthesis

Exclusion Criteria:

  • Known prosthesis infection
  • Pregnancy / Breast feeding
  • Oral bisphosphonate therapy (current use, previous use within the last 12 months, previous 3 or more years cumulative use)
  • Administration of intravenous bisphosphonate, fluoride or strontium within the last 5 years
  • Participation in ongoing or previous denosumab clinical trials
  • Administration of any of the following treatments within the last 12 months
  • TH or PTH derivatives, eg, teriparatide
  • anabolic steroids or testosterone
  • glucocorticosteroids (> 5 mg prednisone equivalent per day for more than 10 days)
  • systemic hormone replacement therapy
  • selective estrogen receptor modulators (SERMs), eg, raloxifene tibolone, calcitonin or calcitriol
  • Any subject in whom denosumab is contraindicated according to the local SmPC of denosumab (SC 60 mg every 6 months in UK)
  • Current hypocalcemia (albumin adjusted serum calcium below 2.13 mmol/L)
  • History of rheumatoid arthritis
  • History of Paget's disease
  • Malignancy (except basal cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years
  • Renal insufficiency assessed by eGFR <30
  • Known sensitivity to mammalian cell derived drug products
  • 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
  • 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
  • Evidence of alcohol or substance abuse within the last 12 months that the Investigator believes would interfere with understanding or completing the study
  • 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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01358669

Contacts
Contact: J M Wilkinson, PhD, FRCS (Tr&Orth) j.m.wilkinson@sheffield.ac.uk

Locations
United Kingdom
Academic Unit of Bone Metabolism Recruiting
Sheffield, South Yorkshire, United Kingdom, S5 7AU
Contact: Tracey S Higginbottom    01142715238 ext 15238    Tracey.Higginbottom@sth.nhs.uk   
Principal Investigator: J M Wilkinson, PhD, FRCS (Tr&Orth)         
Sponsors and Collaborators
Sheffield Teaching Hospitals NHS Foundation Trust
Amgen
University of Sheffield
Investigators
Principal Investigator: J M Wilkinson, PhD, FRCS (Tr&Orth) Sheffield Teaching Hospitals NHS Foundation Trust/University of Sheffield
  More Information

No publications provided

Responsible Party: Sheffield Teaching Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT01358669     History of Changes
Other Study ID Numbers: STH15714
Study First Received: May 11, 2011
Last Updated: December 14, 2012
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Sheffield Teaching Hospitals NHS Foundation Trust:
Denosumab
Total Hip Arthroplasty

ClinicalTrials.gov processed this record on October 30, 2014