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Trial registered on ANZCTR


Registration number
ACTRN12617000937314
Ethics application status
Approved
Date submitted
21/06/2017
Date registered
28/06/2017
Date last updated
30/06/2024
Date data sharing statement initially provided
22/05/2019
Date results provided
17/06/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Novel treatment of acute Charcot foot using the medication denosumab combined with immobilisation.
Scientific title
Effect of denosumab in acute Charcot neuropathic osteoarthropathy on inflammation and on bone health using calcaneal quantitative ultrasound: a phase II randomised controlled trial.
Secondary ID [1] 292174 0
None
Universal Trial Number (UTN)
U1111-1197-8876
Trial acronym
CRUSADES: Charcot foot quantitative ultrasound and denosumab study.
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Charcot neuropathic osteoarthropathy 303649 0
Diabetes mellitus 303650 0
Condition category
Condition code
Musculoskeletal 303037 303037 0 0
Other muscular and skeletal disorders
Metabolic and Endocrine 303038 303038 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Denosumab plus immobilisation.
Denosumab 60 mg subcutaneously will be administered at baseline and then again after six months if clinical evidence of inflammation persists.
The immobilisation device (e.g. total contact cast, Aircast boot) will be applied by an appropriately qualified medical professional at the participant's recruitment site. Standard care and follow up of participants, including management of immobilisation, will be provided by the recruitment site. Immobilisation will be continued until resolution of acute Charcot neuropathic osteoarthropathy (CN).
Intervention code [1] 298333 0
Treatment: Drugs
Intervention code [2] 298334 0
Treatment: Devices
Comparator / control treatment
Immobilisation only.
The immobilisation device (e.g. total contact cast, Aircast boot) will be applied by an appropriately qualified medical professional at the participant's recruitment site. Standard care and follow up of participants, including management of immobilisation, will be provided by the recruitment site. Immobilisation will be continued until resolution of acute Charcot neuropathic osteoarthropathy (CN).
Control group
Active

Outcomes
Primary outcome [1] 302417 0
Time to normalisation of foot temperature (< 2 degrees Celsius maximal difference) measured by infrared thermographic scanner comparing the acute CN foot to the contralateral foot.
Timepoint [1] 302417 0
Standard care visits (as scheduled by treating High Risk Foot Service). Study visits at baseline, 1, 6, 12 and 18 months.
Primary outcome [2] 302419 0
Bone health as assessed by calcaneal quantitative ultrasound parameters (BUA, SOS, stiffness index) comparing the acute CN foot to the contralateral foot, in those receiving immobilisation plus denosumab versus immobilisation alone.
Timepoint [2] 302419 0
Baseline, 1, 6, 12 and 18 months.
Secondary outcome [1] 335910 0
Time of immobilisation as directed by treating High Risk Foot Service.
Timepoint [1] 335910 0
Continuously assessed from baseline until 18 months.
Secondary outcome [2] 335911 0
Change in maximal difference in foot temperature measured by infrared thermographic scanner comparing the acute CN foot to the contralateral foot.
Timepoint [2] 335911 0
Baseline, 1, 6, 12 and 18 months.
Secondary outcome [3] 335912 0
Change in inflammatory markers (ESR, CRP).
Timepoint [3] 335912 0
Baseline, 1, 6, 12 and 18 months.
Secondary outcome [4] 336078 0
Change in bone turnover markers (P1NP, CTX).
Timepoint [4] 336078 0
Baseline, 1, 6, 12 and 18 months.
Secondary outcome [5] 336079 0
Progression of deformity on plain X-ray.
Timepoint [5] 336079 0
Baseline, 6, 12 and 18 months
Secondary outcome [6] 336080 0
Quality of life measured by 36-Item Short Form Survey Instrument (SF-36).
Timepoint [6] 336080 0
Baseline and 12 months.

Eligibility
Key inclusion criteria
* Pre-existing diagnosis of diabetes mellitus
* Ambulant
* Willingness to provide written consent and to participate in study
* Peripheral neuropathy confirmed with monofilament
* Acute CN confirmed radiologically, significantly higher temperature in affected foot compared to contralateral foot (greater than 2 degrees Celsius maximal difference), and less than or equal to 3 months since symptoms onset
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Unable to provide informed consent
* Previous or planned (within subsequent 18 months) osteotomy or surgical fixation involving the foot
* Previous or planned (within subsequent 18 months) lower limb amputation above level of ankle
* Non-weight bearing for greater than 2 month period during past year
* Antiresorptive therapy during past 12 months, and/or greater than 5 year cumulative exposure
* Pre-existing diagnosis of peripheral arterial disease, or impalpable pedal pulses
* Heal ulceration at site of calcaneal quantitative ultrasound probe
* Other acute foot disease: ulceration (>1A on Texas Classification) or infection
* Vitamin D deficiency (25-hydroxyvitamin D < 50 nmol/L) if sufficiency cannot be rapidly achieved by supplementation
* Hypocalcaemia (corrected calcium < 2.10 mmol/L)
* Active dental infection, invasive dental procedure within preceding 3 months, planned invasive dental procedure within subsequent year, other dental contraindication to antiresorptive therapy
* Women lactating, pregnant or of childbearing potential not using contraception
* Life expectancy less than 2 years

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation to ensure 1:1 allocation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
This study is adequately powered to detect baseline differences in estimated bone mineral density (BMD) using calcaneal quantitative ultrasound comparing the acute CN foot to the contralateral foot. Using the standard deviation and effect size published by Sinacore et al (2008) and Petrova & Edmonds (2010), 35 and 24 participants respectively would be needed to have an 80% chance of detecting a baseline difference in estimated BMD at the two-sided 5% significance level.

No previous studies have monitored calcaneal quantitative ultrasound parameters in acute CN during treatment with an antiresorptive drug. Calculated from our unpublished data in people with diabetes, this study will have an 80% chance of detecting a difference in BUA of 17.1 db/MHz at the two-sided 5% significance level. Of note, Pitocco et al (2005) found BMD using dual-energy X-ray absorptiometry significantly increased in the acute CN foot of 11 participants after 6 months of oral bisphosphonate therapy.

Data will be collated using Microsoft Excel. Descriptive data will include medians, means and standard deviations. Data analysis will otherwise be performed using GraphPad Prism 7.0 (GraphPad Software Inc, San Diego, CAL, USA) software. Differences between groups will be analysed with t-test or analysis of variance (ANOVA). Correlations will be analysed using multiple linear regression.

References:
1. Sinacore DR, Hastings MK, Bohnert KL, Fielder FA, Villarreal DT, Blair VP 3rd, Johnson JE. Inflammatory osteolysis in diabetic neuropathic (charcot) arthropathies of the foot. Phys Ther 2008; 88(11): 1399-407.
2. Petrova NL, Edmonds ME. A prospective study of calcaneal bone mineral density in acute Charcot osteoarthropathy. Diabetes Care 2010; 33(10): 2254-6.
3. Pitocco D, Ruotolo V, Caputo S, Mancini L, Collina CM, Manto A, Caradonna P, Ghirlanda G. Six-month treatment with alendronate in acute Charcot neuroarthropathy: a randomized controlled trial. Diabetes Care 2005; 28(5): 1214-5.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/08/2017
Actual
28/05/2018
Date of last participant enrolment
Anticipated
1/06/2022
Actual
20/09/2021
Date of last data collection
Anticipated
20/03/2023
Actual
20/03/2023
Sample size
Target
40
Accrual to date
Final
26
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 8341 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 10811 0
Blacktown Hospital - Blacktown
Recruitment hospital [3] 10812 0
Nepean Hospital - Kingswood
Recruitment hospital [4] 10813 0
Prince of Wales Hospital - Randwick
Recruitment hospital [5] 10814 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [6] 10815 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [7] 10816 0
St George Hospital - Kogarah
Recruitment hospital [8] 10817 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 16411 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 22551 0
2148 - Blacktown
Recruitment postcode(s) [3] 22552 0
2747 - Kingswood
Recruitment postcode(s) [4] 22553 0
2031 - Randwick
Recruitment postcode(s) [5] 22554 0
2065 - St Leonards
Recruitment postcode(s) [6] 22555 0
2050 - Camperdown
Recruitment postcode(s) [7] 22556 0
2217 - Kogarah
Recruitment postcode(s) [8] 22557 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 296712 0
Other
Name [1] 296712 0
Philanthropic donation for diabetes-related foot research
Country [1] 296712 0
Australia
Funding source category [2] 299354 0
Other Collaborative groups
Name [2] 299354 0
The Garvan Institute of Medical Research, Diabetes and Metabolism Division
Country [2] 299354 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Garvan Institute of Medical Research
Address
384 Victoria Street
Darlinghurst NSW 2010
Country
Australia
Secondary sponsor category [1] 295689 0
None
Name [1] 295689 0
Address [1] 295689 0
Country [1] 295689 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297939 0
St Vincent's Hospital HREC
Ethics committee address [1] 297939 0
Ethics committee country [1] 297939 0
Australia
Date submitted for ethics approval [1] 297939 0
24/03/2017
Approval date [1] 297939 0
06/06/2017
Ethics approval number [1] 297939 0
HREC/17/SVH/116

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75522 0
Dr Joel Lasschuit
Address 75522 0
Garvan Institute of Medical Research
384 Victoria Street
Darlinghurst NSW 2010
Country 75522 0
Australia
Phone 75522 0
+61 2 8382 1111
Fax 75522 0
Email 75522 0
[email protected]
Contact person for public queries
Name 75523 0
Joel Lasschuit
Address 75523 0
Garvan Institute of Medical Research
384 Victoria Street
Darlinghurst NSW 2010
Country 75523 0
Australia
Phone 75523 0
+61 2 8382 1111
Fax 75523 0
Email 75523 0
[email protected]
Contact person for scientific queries
Name 75524 0
Katherine Tonks
Address 75524 0
Garvan Institute of Medical Research
384 Victoria Street
Darlinghurst NSW 2010
Country 75524 0
Australia
Phone 75524 0
+61 2 8382 1111
Fax 75524 0
Email 75524 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Publication of IPD was not part of the original ethics approval.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.