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Trial registered on ANZCTR


Registration number
ACTRN12621000085875p
Ethics application status
Submitted, not yet approved
Date submitted
2/11/2020
Date registered
1/02/2021
Date last updated
1/02/2021
Date data sharing statement initially provided
1/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of Zoledronic Acid or Denosumab on Bone Loss in Critically Ill Women – A Randomised Controlled Trial
Scientific title
Effect of Zoledronic Acid or Denosumab on Bone Loss in Critically Ill Women – A Randomised Controlled Trial
Secondary ID [1] 302446 0
NCT04608630
Universal Trial Number (UTN)
U1111-1260-2290
Trial acronym
Bone Zone
Linked study record
Not Applicable

Health condition
Health condition(s) or problem(s) studied:
Critical illness 319268 0
Osteoporosis 319981 0
Condition category
Condition code
Musculoskeletal 317235 317235 0 0
Osteoporosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The three interventions to be examined in this trial is the subcutaneous administration of denosumab 60mg (Arm 1), intravenous administration of zoledronic acid 5mg (Arm 2) and placebo (0.9% saline) (Arm 3). Participants will be randomised to one arm of the trial. The first dose of trial drug will be administered when the patient is deemed to have recovered from their acute illness and is being considered for discharge from ICU in the next 24-48 hours or is in a chronic phase of critical illness. This day of trial drug administration is Day 0.
Vitamin D supplementation: Following enrolment and randomisation, an intramuscular (IM) bolus supplement of 50,000 IU will be administered on the day prior to trial drug administration. This will be followed by an oral (PO) daily dose of 1000 IU for the duration of the study. If the baseline level is found to be <30 nmol/L, an additional dose of 50,000 IU will be administered at that time. If the baseline level is found to be >100 nmol/L, daily oral vitamin D supplementation will be ceased. At 6 months after enrolment patients will be asked to return to the hospital, at which time patients in the denosumab arm of the study will receive another injection of this drug, while the other two groups will receive a placebo injection
Denosumab:
Formulation: 60mg in a single-use 1ml syringe
Administration: subcutaneous injection administered in upper arm, upper thigh, or abdomen.
Frequency: 6 monthly
Zoledronic acid:
Formulation: 5mg in 100ml bag of 0.9% Saline of 5% Dextrose
Administration: intravenous infusion over at least 15 minutes
Frequency: once only
Following administration of the study drug, monitoring for hypocalcaemia will occur at least daily for 48 hours. The majority of patients will have intra-arterial and/or central venous vascular access, with regular blood gas measurement that include calcium performed. If routine testing provides twice-daily calcium additional testing will not be performed. Hypocalcaemia is defined as ionized calcium <0.9 mmol/L, based on ICU protocols for treatment of hypocalcaemia in other settings, ie. citrate induced hypocalcaemia with the use of citrate for anticoagulation. Hypocalcaemia will be treated with parenteral calcium, as per hospital dosing and administration protocols, to maintain a target ionized calcium range of 0.9-1.1 mmol/L.
The second dose of trial drug and/or placebo will be administered at 6 months.
All sites will be monitored by the Bone Zone Project manager or delegate to ensure the trial intervention is delivered as described. At this time participant hospital records (including pathology reports, bone densitometry reports, medication charts, progress notes) will be reviewed.
A subset of participants will be included in a nested bone turnover marker and pathology sub study. 50 participants from each arm will be included in the sub study. The first 50 participants from each arm who are enrolled at a participating site and provide consent to participate in the sub study will be included.
Intervention code [1] 318736 0
Treatment: Drugs
Comparator / control treatment
Placebo:
Formulation:
0.9% Saline in a single-use 1ml syringe
Administration: subcutaneous injection administered in upper arm, upper thigh, or abdomen
and/or
0.9% Saline 100ml bag
AdministrationL intravenous infusion administered over at least 15 minutes
Patients allocated to Arm 1 denosumab will also receive an intravenous placebo infusion at Day 0
Patients allocated to Arm 2 zoledronic acid will also receive a subcutaneous placebo injection at Day 0
Participants allocated to Arm 3 placebo will receive a subcutaneous placebo injection at Day 0 and 6 months and an intravenous placebo infusion at Day 0.
Standard Care
Standard nutrition will be administered to both control and treatment arm participants per ICU feeding protocols, including dietician review and advice provided to participants in hospital.
Vitamin D supplementation: Following enrolment and randomisation, an intramuscular (IM) bolus supplement of 50,000 IU will be administered on the day prior to study drug administration. This will be followed by an oral (PO) daily dose of 1000 IU for the duration of the study. If the baseline level is found to be <30 nmol/L, an additional dose of 50,000 IU will be administered at that time.If the baseline level is found to be >100 nmol/L, daily oral vitamin D supplementation will be ceased.
Control group
Placebo

Outcomes
Primary outcome [1] 325302 0
Annualised change in femoral neck bone mineral density (BMD) for the year after ICU discharge
Timepoint [1] 325302 0
Measured at first Bone Mineral Densitometry scan conducted within 28 days of trial drug administration and one year after the first BMD scan.
Secondary outcome [1] 387446 0
Annualised change in lumbar-spine on Bone Mineral Densitometry scan in the year after critical illness.
Timepoint [1] 387446 0
Measured at first Bone Mineral Densitometry scan conducted within 28 days of trial drug administration and one year after the first BMD scan
Secondary outcome [2] 387447 0
Clinical fragility fracture
Information on the date, site, and circumstance of the fracture obtained by interview and X-ray report sought and confirmed by medical report.
Timepoint [2] 387447 0
Self-reported incident clinical fractures obtained at 6 month and 1 year follow-up visits.
Secondary outcome [3] 387448 0
Vertebral fracture assessed by BMD scan
Timepoint [3] 387448 0
Measured at first Bone Mineral Densitometry scan conducted within 28 days of trial drug administration and one year after the first BMD scan
Secondary outcome [4] 387449 0
Falls
Timepoint [4] 387449 0
Self-reported falls between hospital discharge and 6 months will be obtained at the 6 month post trial drug administration follow up visit and between 6 months and 1 year timepoints at the 1 year post trial drug administration follow-up visit.
Secondary outcome [5] 387450 0
Hospital readmissions
Timepoint [5] 387450 0
Self-reported hospital readmissions between hospital discharge and 6 months will be obtained at the 6 month post trial drug administration follow up visit and between 6 months and 1 year timepoints at the 1 year post trial drug administration follow-up visit.
Secondary outcome [6] 387451 0
Incidence of serious adverse events defined as, severe hypocalcaemia, new infection, osteonecrosis, following administration of the first dose of trial drug. This will be assessed through a combination of in-person and telephone follow up and verification of medical records provided by health service or treating medical practitioner.
Timepoint [6] 387451 0
Following administration of the first dose of trial drug until 12 months post administration.
Secondary outcome [7] 387452 0
Quality of life will be measured using the EuroQol 5D-5L (EQ5D-5L)
Timepoint [7] 387452 0
Quality of life will be assessed at baseline and on the day of the 6 month post trial drug administration follow up visit and day of the 1 year post trial drug administration follow-up visit.
Secondary outcome [8] 387453 0
Health Economic Analysis using hospital costing, we will establish the cost per fracture prevented, and cost per health-related quality of life adjusted years (QALYs)
Timepoint [8] 387453 0
Calculated over study period
Secondary outcome [9] 387454 0
Change in the serum bone turnover marker collagen type 1 cross-linked c-telopeptide (CTX) measured using the automated Roche Modular Analytics E170 analyser. Serum collagen type 1 cross-linked c- telopeptide limit of detection was 10 ng/L with inter-assay coe cient of variations (CVs) of 6.5% at 361 ng/L, 3.8% at 816 ng/L and 3.4% at 3304 ng/L.
Timepoint [9] 387454 0
Assessed in 150 participants in a nested sub-study
The pathology assessments will be collected at 7, Day 28, 6 months and 1 year post trial drug administration.
Secondary outcome [10] 387455 0
Change in serum bone resorption marker type 1 N-terminal procollagen (P1NP) measured using the automated Roche Modular Analytics E170 analyser. Serum type 1 N-terminal procollagen inter-assay CVs were 4.9% at 73 microgramg/L, 2.6% at 392 microgramg/L, and 2.1% at 768 microgramg/L (n = 10) with a limit of detection of 5 microgramg/L.
Timepoint [10] 387455 0
Assessed in 150 participants in a nested sub-study
The pathology assessments will be collected at 7, Day 28, 6 months and 1 year post trial drug administration.
Secondary outcome [11] 387456 0
Mortality
Will be determined by telephone follow up, review of health service medical records, follow up with participant General Practitioner
Timepoint [11] 387456 0
1 year post trial drug administration

Eligibility
Key inclusion criteria
Female
Age > 50 years
Has been in ICU for 2 or more calendar days and is not expected to be discharged from ICU today
Has required ICU level support (i.e. intravenous vasoactive drugs, or invasive mechanical ventilation, or non-invasive ventilation or high flow nasal oxygen at FiO2>0.4 and/or gas flows >40L/m) for a minimum cumulative duration of 6-hours
Expected to survive the current hospital admission
Minimum age
50 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Active malignancy
Metabolic bone disease
Pregnancy
Current eGFR <30ml/min or receiving renal replacement therapy
Known contraindication to denosumab or zoledronic acid
Increased risk of osteonecrosis (poor dentition or oral hygiene, dental infection)
Known hypoparathyroidism
Current treatment with anti-fracture agent (bisphosphonate, strontium, teriparatide within previous 2 years, or menopausal hormone therapy within previous 12-months or denosumab within previous 6 months)
Current indication for anti-fracture therapy (known BMD T-score <-2.5 and/or known fragility fracture)
Weight >120 kg or unable to undertake BMD for any reason
INR>3 or Platelet count <30,000.

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)
An independent statistician will formulate computer driven randomly allocated sequence generation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A permuted block randomisation method with variable block sizes, stratified by site, will be used to allocate eligible patients to each of the three treatment arms on a 1:1:1 basis.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
To detect a clinically significant 2% absolute difference with 4% SD in annual change in femur BMD, with 90% power, in a 3-sample group looking for a pairwise difference between any 2 of the 3 groups, requires a sample size of 108 per intervention group. With a predicted 15% mortality and 15% loss to follow-up requires an overall sample size of 450 participants.
All data will be assessed for normality. Continuously normally distributed data will be reported as mean (+standard deviation), whereas non-parametric data will be reported using median (interquartile range [IQR]) or frequency distribution. Where normality exists, the primary and secondary outcomes will be analysed using paired t-tests, with a two-sided p-value of 0.05 considered to be statistically significant. Where changes in outcome are found to be non-symmetrical, Wilcoxon sign rank tests will be employed. Due to small sample size, multivariate analysis will not be performed. Before completion of study and database lock, a formal statistical analysis plan will be completed and placed in the public domain.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 17730 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [2] 17731 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [3] 17732 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 31585 0
3220 - Geelong
Recruitment postcode(s) [2] 31586 0
2010 - Darlinghurst
Recruitment postcode(s) [3] 31587 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 306875 0
Government body
Name [1] 306875 0
Department of Health
Address [1] 306875 0
Department of Health
GPO Box 9848
Canberra ACT 2601
Australia
Country [1] 306875 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Monash University
School of Public Health and Preventative Medicine
Australia and New Zealand Intensive Care Research Centre
553 St Kilda Rd
Melbourne, Victoria, 3004
Country
Australia
Secondary sponsor category [1] 307433 0
None
Name [1] 307433 0
Address [1] 307433 0
Country [1] 307433 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307031 0
Austin Health
Ethics committee address [1] 307031 0
145 Studley Road
PO Box 5555
Heidelberg Victoria 3084
Ethics committee country [1] 307031 0
Australia
Date submitted for ethics approval [1] 307031 0
30/09/2020
Approval date [1] 307031 0
Ethics approval number [1] 307031 0

Summary
Brief summary
Women over 50 years of age who require admission to an Intensive Care Unit (ICU), lose bone at a significantly higher rate compared to women who do not become critically ill. Zoledronic acid and denosumab are medications that prevent bone breakdown but are not commonly used in the ICU population. This trial aims to study the effects of these medications, compared to placebo, on bone density in 450 critically ill women aged 50 years of age or greater. Participants will be allocated to receive one of the medications listed or a placebo. Participants will have a bone density scan after trial drug is administered and again at 12 months and have information such as falls, fractures hospital readmissions and quality of life collected at 6 and 12 months. A smaller group of participants, with prior consent will be enrolled to have some additional blood tests to measure markers of bone breakdown in the blood.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105790 0
A/Prof Neil Orford
Address 105790 0
Barwon Health, University Hospital Geelong
Intensive Care Unit, Baxter Wing Level 4
PO Box 281
Geelong Victoria 3220
Country 105790 0
Australia
Phone 105790 0
+61 3 4215 1723
Fax 105790 0
+61 3 4215 1761
Email 105790 0
n.orford@deakin.edu.au
Contact person for public queries
Name 105791 0
Ms Allison Bone
Address 105791 0
ANZIC-RC
Department of Epidemiology and Preventive Medicine
Monash University
Level 3
553 St Kilda Road
Melbourne VIC 3004
Country 105791 0
Australia
Phone 105791 0
+61 3 9903 0343
Fax 105791 0
Email 105791 0
Allison.Bone@monash.edu
Contact person for scientific queries
Name 105792 0
A/Prof Neil Orford
Address 105792 0
Barwon Health, University Hospital Geelong
Intensive Care Unit, Baxter Wing Level 4
PO Box 281
Geelong Victoria 3220
Country 105792 0
Australia
Phone 105792 0
+61 3 4215 1723
Fax 105792 0
+61 3 4215 1761
Email 105792 0
n.orford@deakin.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All de­-identified individual patient data as per the data sharing policy of the ANZIC­ RC, Monash University
When will data be available (start and end dates)?
Two years after publication of the primary manuscript. No end date.
Available to whom?
Researchers who provide a methodically sound scientific proposal as per data sharing policy of the ANZIC­ RC, Monash University
Available for what types of analyses?
Only to achieve the aims of the approved proposal
How or where can data be obtained?
Access subject to approval by the Australian and New Zealand Intensive Care Research Centre. anzicrc@monash.edu
What supporting documents are/will be available?
No other documents available
Summary results
No Results