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Trial registered on ANZCTR


Trial ID
ACTRN12617000545369
Ethics application status
Approved
Date submitted
21/03/2017
Date registered
18/04/2017
Date last updated
7/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of denosumab on bone turnover markers in critically ill women
Scientific title
Effect of denosumab on bone turnover markers in critically ill women - A safety and feasibility, randomised, placebo controlled trial
Secondary ID [1] 291499 0
None
Universal Trial Number (UTN)
U1111-1194-4990
Trial acronym
SOFTER (Skeletal Outcomes after Intensive Care)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critical illness 302572 0
Osteoporosis 302573 0
Condition category
Condition code
Musculoskeletal 302097 302097 0 0
Osteoporosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention to be examined in this trial is the subcutaneous administration of denosumab 60mg compared to placebo (0.9% saline). The first dose of study drug will be given on day 3 in ICU after vitamin D assessment has been completed and supplementation provided, and in the absence of untreated or new infection. The second dose of intervention or placebo will be administered at the 6-month follow-up, after vitamin D assessment and supplementation as indicated.

The first dose of study drug will be administered by an ICU registered nurse as a subcutaneous injection on study day 3 in ICU.

Denosumab:
*Formulation: 60mg denosumab in a single-use pre-filled 1ml syringe
*Administration: subcutaneous injection administered in upper arm, upper thigh, or abdomen.

Following administration of the study drug in ICU, monitoring for hypocalcaemia will occur a minimum of twice 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 study drug will be administered by a registered nurse as a subcutaneous injection at 6-months post-ICU discharge.
Intervention code [1] 297568 0
Treatment: Drugs
Comparator / control treatment
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, a serum vitamin D level will be collected and analysed. If the serum vitamin D level is < 50 mol/L, a single dose of 50,000 IU cholecalciferol will be administered via oral or enteral route.

Placebo:
*Formulation: 0.9% Saline in a single-use pre-filled 1ml syringe
*Administration: subcutaneous injection administered in upper arm, upper thigh, or abdomen.

Control group
Placebo

Outcomes
Primary outcome [1] 301543 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 coefficient of variations (CVs) of 6.5% at 361 ng/L, 3.8% at 816 ng/L and 3.4% at 3304 ng/L (n = 10).
Timepoint [1] 301543 0
28-days after administration of study drug dose 1
Secondary outcome [1] 332953 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 microgram/L, 2.6% at 392 microgram/L, and 2.1% at 768 microgram/L (n = 10) with a limit of detection of 5 microgram/L.
Timepoint [1] 332953 0
1-year after administration of study drug dose 1
Secondary outcome [2] 332954 0
Annualised change in lumbar-spine BMD measured by DEXA scan
Timepoint [2] 332954 0
1-year after administration of study drug dose 1
Secondary outcome [3] 332955 0
Incidence of serious adverse events (severe hypocalcaemia, new infection, and osteonecrosis jaw, assessed through examination, review of laboratory results, and review of participant medical records)
Timepoint [3] 332955 0
28-days after administration of study drug dose 1
Secondary outcome [4] 332956 0
Fragility fracture (ascertained through interrogation of radiological database and participant electronic medical record)
Timepoint [4] 332956 0
1-year after administration of study drug dose 1
Secondary outcome [5] 333269 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 [5] 333269 0
28-days after administration of study drug dose 1
Secondary outcome [6] 333270 0
Change in 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 coefficient of variations (CVs) of 6.5% at 361 ng/L, 3.8% at 816 ng/L and 3.4% at 3304 ng/L (n = 10).
Timepoint [6] 333270 0
1-year after administration of study drug dose 1
Secondary outcome [7] 333271 0
Annualised change in proximal femur BMD measured by DEXA scan
Timepoint [7] 333271 0
1-year after administration of study drug dose 1
Secondary outcome [8] 333272 0
Mortality (ascertained through interrogation of hospital database and participant follow-up)
Timepoint [8] 333272 0
1-year after administration of study drug dose 1

Eligibility
Key inclusion criteria
1. Admitted to ICU
2. Female
3. Age >50 years or postmenopausal (amenorrhea for greater than 6-months or serum FSH >40mIU/L) or Age < 50 years with bilateral salpingo-oopherectomy
4. Expected duration of mechanical ventilation > 24 hrs
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Unable to undertake BMD (weight >120kg, impaired mobility)
2. Active malignancy
3. Currently receiving immunosuppressive agents
4. Metabolic bone disease
5. Pregnancy
6. eGFR <30ml/min
7. Known contraindication to denosumab (previous reaction, osteonecrosis of the jaw, atypical femoral fracture)
8. Increased risk of osteonecrosis (poor dentition or oral hygiene, dental infection)
9. Hypocalcaemia (<0.9 mm/L ionized calcium)
10. Hypoparathyroidism
11. Malabsorption sydnromes / extensive small bowel resection
12. Neurological condition likely to prevent weight-bearing (eg severe traumatic brain injury, stroke with loss of mobility, degenerative neurological disease)
13. Current treatment with anti-fracture agent (bisphosphonate, denosumab, strontium, teriparatide, within previous 2 years)
14. Current indication for anti-fracture therapy (known BMD T-score < -2.5 and fragility fracture)
15. Treatment limitations in place

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)
Allocation involved contacting the holder of the allocation schedule who was "off-site" or at central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
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
The principal aim of this study is to detect the change in the bone resorption marker CTX in participants receiving denosumab compared to those receiving placebo. A prospective RCT conducted in 20 postmenopausal females with chronic critical illness administered 3mg ibandronate intravenously compared to placebo, and followed patients for 14-days. They observed a 34% decrease in serum CTX levels on day 6 compared to a 13% increase in the placebo group. By day 11 there was no difference. A large RCT of denosumab for fracture prevention in women with osteoporosis reported a median decrease of serum CTX of 86% at 1-month compared to placebo. In our prospective study of bone turnover markers and BMD in ICU survivors, we reported a median CTX of 654 [IQR 479–1165 ng/] at baseline, and 315 [162-592 ng/L] at 1-year in female participants, with a population median of 338 ng/L (IQR 212–499)..

Given these results we believe a clinically significant effect of denosumab is a 50% reduction in median serum CTX from baseline levels to day 28, compared to no change in the placebo group. A sample size of 7 patients per group will provide a 95% power (2 sided p-value of 0.05) to detect a difference in serum CTX from day 0 to day 28 equal to 2 standard deviations, and an 80% power (2 sided p-value of 0.05) to detect a difference equal to 1.5 standard deviations. With a predicted 20% rate of drop-out or death from enrolment to the 28-day primary outcome time-point, a sample size of 18 participants is required. This figure equates to the anticipated enrollment over a 12-month period at the principal study site.

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.

Recruitment
Recruitment status
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)
VIC
Recruitment hospital [1] 7696 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment postcode(s) [1] 15618 0
3220 - Geelong

Funding & Sponsors
Funding source category [1] 295981 0
Charities/Societies/Foundations
Name [1] 295981 0
Intensive Care Foundation
Address [1] 295981 0
Level 2, 10 Ievers Terrace
Carlton, Victoria, 3053
Australia
Country [1] 295981 0
Australia
Primary sponsor type
Hospital
Name
University Hospital Geelong
Address
Ryrie St
Geelong, 3220
VIC
Country
Australia
Secondary sponsor category [1] 294872 0
None
Name [1] 294872 0
Address [1] 294872 0
Country [1] 294872 0
Other collaborator category [1] 279493 0
University
Name [1] 279493 0
Australian and New Zealand Intensive Care Research Centre, Department of Epdiemiology and Preventive Medicine, Monash University
Address [1] 279493 0
Level 3
533 St Kilda Rd
Melbourne
VIC 3004
Country [1] 279493 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297247 0
Barwon Health REGI
Ethics committee address [1] 297247 0
PO Box 281
Geelong
VIC 3220
Ethics committee country [1] 297247 0
Australia
Date submitted for ethics approval [1] 297247 0
21/03/2017
Approval date [1] 297247 0
27/02/2018
Ethics approval number [1] 297247 0

Summary
Brief summary
Intensive care patients face health issues that extend beyond their critical illness, including weakness, changes in quality of life, and an increase likelihood of disease and death. One area of post-ICU illness that may be preventable is fragility fracture.

Fragility fractures occur due to weakening of bone, most commonly due to osteoporosis in postmenopausal women. Fragility fractures have devastating effects, resulting in hospitalisation, loss of independence and function, and increased likelihood of dying in the following year.

Critical illness appears to increase the rate of bone loss, with studies showing an increased in markers of bone turnover, an accelerated loss of bone mass, and an increase in rate of fragility fractures, during and after critical illness. This is particularly evident in women, suggesting critically ill women face an extra injury to their bones at a time when they are already at risk.

Medications that prevent or reduce bone loss have been extensively tested and shown to be effective in post-menopausal women, and other groups at risk of losing bone rapidly. This includes some types of cancer, and patients receiving therapies that cause bone loss.

There is very limited experience in using these antiresorptive medications in critical illness, although some evidence suggests they may be effective at reducing bone turnover.
Denosumab is a more recent antiresorptive medication that acts to prevent bone loss, and has been shown to be effective in large trials. It has not be used in critical illness, so we would like to perform a small study to ensure it is safe and effective in this group. Like other antiresorptive agents denosumab has side effects, although its has an advantage that it does not affect kidney function. It does however have some effect on immune function, a concern during critical illness. Given this we plan to delay its administration until there is no active infection.

At the completion of this study we will examine the safety and effect of densoumab on bone turnover in postmenopausal critically ill women. If it appears safe and show signs of benefit, we will plan a larger study to assess its effect on bone mass, fractures, and survival, more completely.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 1601 1601 0 0

Contacts
Principal investigator
Name 73454 0
A/Prof Neil Orford
Address 73454 0
Intensive Care Unit
Level 4
University Hospital Geelong
Ryrie St
Geelong
VIC 3220
Country 73454 0
Australia
Phone 73454 0
+61342151722
Fax 73454 0
+61342151761
Email 73454 0
neilo@barwonhealth.org.au
Contact person for public queries
Name 73455 0
Ms Rosemary Finnemore
Address 73455 0
Intensive Care Unit
Level 4
University Hospital Geelong
Ryrie St
Geelong
VIC 3220
Country 73455 0
Australia
Phone 73455 0
+61342151761
Fax 73455 0
+61342151761
Email 73455 0
rosef@barwonhealth.org.au
Contact person for scientific queries
Name 73456 0
A/Prof Neil Orford
Address 73456 0
Intensive Care Unit
Level 4
University Hospital Geelong
Ryrie St
Geelong
VIC 3220
Country 73456 0
Australia
Phone 73456 0
+61342151761
Fax 73456 0
+61342151761
Email 73456 0
neilo@barwonhealth.org.au