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Protocol
Protocol for a randomised control trial of bisphosphonate (zoledronic acid) treatment in childhood femoral head avascular necrosis due to Perthes disease
  1. Kamal Jamil1,2,3,
  2. Margaret Zacharin4,
  3. Bruce Foster5,
  4. Geoffrey Donald6,
  5. Timothy Hassall7,
  6. Aris Siafarikas8,9,
  7. Michael Johnson10,
  8. Elaine Tham11,
  9. Colin Whitewood12,
  10. Val Gebski13,
  11. Chris T Cowell1,14,
  12. David Graham Little1,2,
  13. Craig Frank Munns1,15
  1. 1 Discipline of Child and Adolescent Health, The Children’s Hospital at Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
  2. 2 Department of Orthopaedic Research and Biotechnology, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia
  3. 3 Medical Faculty, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
  4. 4 Department of Endocrinology, Murdoch Children’s Research Institute, The Royal Children’s Hospital Melbourne, Melbourne, Victoria, Australia
  5. 5 Department of Orthopaedic Surgery, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia
  6. 6 Department of Orthopaedic, Lady Cilento Children’s Hospital, South Brisbane, Queensland, Australia
  7. 7 Department of Oncology, Lady Cilento Children’s Hospital, South Brisbane, Queensland, Australia
  8. 8 Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
  9. 9 School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia
  10. 10 Department of Orthopaedics, The Royal Children’s Hospital Melbourne, Melbourne, Victoria, Australia
  11. 11 Department of Endocrinology and Diabetes, Women’s and Children’s Hospital Adelaide, North Adelaide, South Australia, Australia
  12. 12 Department of Orthopaedic Surgery, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
  13. 13 NHRMC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia
  14. 14 Kids Research Institute, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia
  15. 15 Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia
  1. Correspondence to Dr Kamal Jamil; mmuh8186{at}uni.sydney.edu.au

Abstract

Introduction Perthes disease (PD) is an idiopathic disorder presenting with avascular necrosis to the femoral head, which frequently results in flattening. Long-term function is directly related to the subsequent femoral head sphericity. Current treatment includes mechanical modalities and surgical procedures, which are therapeutic but are not uniformly able to prevent collapse. The use of the nitrogen-containing bisphosphonate zoledronic acid (ZA) to inhibit osteoclastic bone resorption is aimed at preserving femoral head strength, reducing collapse and thus maintaining shape. The proposed multicentre, prospective, randomised controlled trial intends to evaluate the efficacy of ZA treatment in PD.

Methods and analysis An open-label randomised control trial recruiting 100 children (50 each treatment arm) 5 to 16 years old with unilateral PD. Subjects are randomly assigned to either (a) ZA and standard care or (b) Standard care. The primary outcome measure is deformity index (DI), a radiographic parameter of femoral head roundness assessed at 24 months, following 12 months of ZA treatment (3-monthly doses of ZA 0.025 mg/kg at baseline, 3, 6, 9 and 12 months) plus 12 months observation (group A) or 24 months of observation (group B). Secondary outcome measures are femoral head subluxation, Faces Pain scale, Harris hip score and quality of life. Assessments are made at baseline, 3 monthly during the first year of follow-up and then 6 monthly, until the 24th month.

Ethics and dissemination The study commenced following the written approval from the Human Research Ethics Committee. Safety considerations regarding the effects of ZA are monitored which include the subject’s symptomatology, mineral status, bone mass and turnover activity, and metaphyseal modelling. Data handling plan requires that all documents, clinical information, biological samples and investigation results will be held in strict confidence by study investigators to preserve its safety and confidentiality.

Trial registration number Australian and New Zealand Clinical Trials ACTRN12610000407099, pre-results.

  • bone metabolism
  • orthopaedics
  • endocrinology
  • bone disease

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/bmjpo-2017-000084

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    Footnotes

    • Contributors CFM, MZ, BF, CTC, DGL and VG participated in all aspects of the conception, design and funding of the study. GD, TH, MJ, ET, CW and AS were responsible to the implementation of the study at their respective site. KJ was responsible for data collection and analysis. All authors were responsible for drafting the manuscript and have read and approved the final manuscript.

    • Funding The study is funded by National Health and Medical Research Council (NHMRC) and Novartis for provision of drug (Alcasta).

    • Competing interests DL was a coinventor of the use of zoledronic acid (ZA) for the indication of avascular necrosis of bone (AVN). CHW is the registered owner of the patent of ZA for this indication and in 2003 licensed to Novartis the commercialisation of this patent. Novartis paid royalties to the SCHN (Westmead) in 2003 and DL was a recipient of a proportion of those royalties as per the hospital’s IP policy. Novartis has decided not to continue the development pathway of clinical trials that would be necessary to demonstrate ZA’s efficacy and safety sufficient to register it as a licensed indication for AVN. For this reason, we have initiated an investigator-led study to determine the efficacy and safety of ZA in children with AVN due to Perthes disease. Novartis have not had input into the design of the study but have agreed to provide the drug at no cost. There is no direct conflict of interest for DL because of the ownership/license arrangement of the patent as listed above, as it has lapsed. DL has provided consultancy services to Novartis in the past. This is not an ongoing relationship but was openly declared. DL has ongoing basic science research collaborations with Novartis, Amgen, Celgene and Acceleron, and N8 medical, relating to various pharmaceutical methods for bone repair. He is not currently undertaking any other study of ZA financed in whole or in part by any pharmaceutical company or other party and will be receiving no financial reimbursement for this study. All other trial investigators are involved only in specialist care of their individual patients and as such have no conflict of interest in this trial.

    • Ethics approval Human Research Ethics Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.