Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000085875
Ethics application status
Approved
Date submitted
2/11/2020
Date registered
1/02/2021
Date last updated
21/07/2024
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 Adults – A Randomised Controlled Trial
Scientific title
Effect of Zoledronic Acid or Denosumab on Bone Loss in Critically Ill Adults – 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 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 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 aged 50 years or older or male aged 70 years or older
Has been in ICU for 2 or more calendar days and is not expected to be discharged from ICU on the second day
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
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Cancer related metastatic bone disease or multiple myeloma
Paget's disease
Pregnancy
Current eGFR <30ml/min or receiving renal replacement therapy
Known contraindication to denosumab or zoledronic acid
Obvious holes in teeth or broken teeth or dental or gum infection
Known untreated hypoparathyroidism
Current treatment with bisphosphonate, strontium or teriparatide within previous 2 years, or menopausal hormone therapy or romosozumab within previous 12-months or denosumab within previous 6 months
Current fragility fracture of hip, spine, femur or forearm
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
Recruiting
Date of first participant enrolment
Anticipated
1/03/2021
Actual
15/07/2021
Date of last participant enrolment
Anticipated
28/02/2026
Actual
Date of last data collection
Anticipated
28/03/2027
Actual
Sample size
Target
450
Accrual to date
146
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,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 hospital [4] 20990 0
The Alfred - Melbourne
Recruitment hospital [5] 20992 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [6] 23315 0
Gold Coast University Hospital - Southport
Recruitment hospital [7] 23316 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [8] 23317 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [9] 23319 0
Launceston General Hospital - Launceston
Recruitment hospital [10] 24897 0
Frankston Hospital - Frankston
Recruitment hospital [11] 24898 0
Box Hill Hospital - Box Hill
Recruitment hospital [12] 24899 0
John Hunter Hospital - New Lambton
Recruitment hospital [13] 24900 0
Prince of Wales Hospital - Randwick
Recruitment hospital [14] 24901 0
St George Hospital - Kogarah
Recruitment hospital [15] 24902 0
Wollongong Hospital - Wollongong
Recruitment hospital [16] 24903 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [17] 24904 0
The Wesley Hospital - Auchenflower
Recruitment hospital [18] 24905 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [19] 24906 0
St John of God Hospital, Murdoch - Murdoch
Recruitment hospital [20] 24907 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [21] 25738 0
Blacktown Hospital - Blacktown
Recruitment hospital [22] 25739 0
Western Hospital - Footscray - Footscray
Recruitment hospital [23] 25740 0
Sunshine Hospital - St Albans
Recruitment postcode(s) [1] 31585 0
3220 - Geelong
Recruitment postcode(s) [2] 31586 0
2010 - Darlinghurst
Recruitment postcode(s) [3] 31587 0
3084 - Heidelberg
Recruitment postcode(s) [4] 35821 0
3004 - Melbourne
Recruitment postcode(s) [5] 35823 0
3065 - Fitzroy
Recruitment postcode(s) [6] 38688 0
4215 - Southport
Recruitment postcode(s) [7] 38689 0
5000 - Adelaide
Recruitment postcode(s) [8] 38690 0
6008 - Subiaco
Recruitment postcode(s) [9] 38692 0
7250 - Launceston
Recruitment postcode(s) [10] 40550 0
3199 - Frankston
Recruitment postcode(s) [11] 40551 0
3128 - Box Hill
Recruitment postcode(s) [12] 40552 0
2305 - New Lambton
Recruitment postcode(s) [13] 40553 0
2031 - Randwick
Recruitment postcode(s) [14] 40554 0
2217 - Kogarah
Recruitment postcode(s) [15] 40555 0
2500 - Wollongong
Recruitment postcode(s) [16] 40556 0
4575 - Birtinya
Recruitment postcode(s) [17] 40557 0
4066 - Auchenflower
Recruitment postcode(s) [18] 40558 0
3050 - Parkville
Recruitment postcode(s) [19] 40559 0
6150 - Murdoch
Recruitment postcode(s) [20] 41562 0
2148 - Blacktown
Recruitment postcode(s) [21] 41563 0
3011 - Footscray
Recruitment postcode(s) [22] 41564 0
3021 - St Albans
Recruitment outside Australia
Country [1] 25902 0
New Zealand
State/province [1] 25902 0
Auckland, Wellington

Funding & Sponsors
Funding source category [1] 306875 0
Government body
Name [1] 306875 0
Department of Health
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
Approved
Ethics committee name [1] 307031 0
Austin Health
Ethics committee address [1] 307031 0
Ethics committee country [1] 307031 0
Australia
Date submitted for ethics approval [1] 307031 0
30/09/2020
Approval date [1] 307031 0
17/03/2021
Ethics approval number [1] 307031 0

Summary
Brief summary
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
[email protected]
Contact person for public queries
Name 105791 0
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
[email protected]
Contact person for scientific queries
Name 105792 0
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
[email protected]

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. [email protected]


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.

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