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Trial registered on ANZCTR

Registration number

ACTRN12617000545369

Ethics application status

Approved

Date submitted

21/03/2017

Date registered

18/04/2017

Date last updated

16/09/2019

Date data sharing statement initially provided

16/09/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Effect of denosumab and zoledronic acid on bone turnover markers in critically ill women

Scientific title

Effect of denosumab and zoledronic acid on bone turnover markers in critically ill women - A safety and feasibility, randomised, placebo controlled trial

Secondary ID [1]

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

Osteoporosis

Condition category

Condition code

Musculoskeletal

Osteoporosis

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The interventions to be examined in this trial are subcutaneous administration of denosumab 60mg six monthly for 1-year, compared to intravenous administration of zoledronic acid 5mg annual dose for 1-year, 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. A second dose of denosumab 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 and intravenous 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.

Zoledronic acid:
*Formulation: 5mg zoledronic acid in a 100 ml single-use normal saline bag.
*Administration: intravenuos infusion via existing vascular access over 15-minutes.

Placebo:
* Denosumab placebo
* Formulation: 0.9% Saline in a single-use pre-filled 1ml syringe
* Administration: Subcutaneous injection administered in upper arm, upper thigh, or abdomen.
* Zoledronic acid placebo
* Formulation: 100 ml single-use normal saline bag
* Administration: intravenuos infusion via existing vascular access over 15-minutes.

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 (densoumab or placebo) will be administered by a registered nurse as a subcutaneous injection at 6-months post-ICU discharge.

Intervention code [1]

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 nmol/L, a single dose of vitamin D will be administered via the oral/enteral or intra-muscular (IM) route. Preference will be given to the oral/enteral route. Oral/enteral supplementation is 50,000 IU cholecalciferol and IM 300,000 IU cholecalciferol.

Control group

Placebo

Outcomes

Primary outcome [1]

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]

28-days after administration of study drug dose 1

Secondary outcome [1]

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]

1-year after administration of study drug dose 1

Secondary outcome [2]

Annualised change in lumbar-spine BMD measured by DEXA scan

Timepoint [2]

1-year after administration of study drug dose 1

Secondary outcome [3]

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]

28-days after administration of study drug dose 1

Secondary outcome [4]

Fragility fracture (ascertained through interrogation of radiological database and participant electronic medical record)

Timepoint [4]

1-year after administration of study drug dose 1

Secondary outcome [5]

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]

28-days after administration of study drug dose 1

Secondary outcome [6]

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]

1-year after administration of study drug dose 1

Secondary outcome [7]

Annualised change in proximal femur BMD measured by DEXA scan

Timepoint [7]

1-year after administration of study drug dose 1

Secondary outcome [8]

Mortality (ascertained through interrogation of hospital database and participant follow-up)

Timepoint [8]

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. Intensive care unit length of stay > 24 hrs

Minimum age

18 Years

Maximum age

No limit

Sex

Females

Can healthy volunteers participate?

Key exclusion criteria

1. Active malignancy
2. Metabolic bone disease
3. Pregnancy
4. Current eGFR <30ml/min
5. Known contraindication to denosumab (previous reaction, osteonecrosis of the jaw, atypical femoral fracture)
6. Increased risk of osteonecrosis (poor dentition or oral hygiene, dental infection)
7. Hypoparathyroidism
8. Malabsorption sydnromes / extensive small bowel resection
9. Current treatment with anti-fracture agent (bisphosphonate, strontium, teriparatide, within previous 2 years or denosumab within previous 6 months)
10. Current indication for anti-fracture therapy (known BMD T-score < -2.5 and fragility fracture)
11. Death is imminent or expected in this hospital admission

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 or zoledronic acid 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 87. 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 80. 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) 18.

Given these results we believe a clinically significant effect of denosumab or zoledronic acid 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 30 participants is required. This figure equates to the anticipated enrolment over an 18-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

1/04/2018

Actual

27/04/2018

Date of last participant enrolment

Anticipated

31/03/2020

Actual

Date of last data collection

Anticipated

30/04/2021

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,VIC

Recruitment hospital [1]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [2]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [3]

St Vincent's Hospital (Darlinghurst) - Darlinghurst

Recruitment postcode(s) [1]

3220 - Geelong

Recruitment postcode(s) [2]

3084 - Heidelberg

Recruitment postcode(s) [3]

2010 - Darlinghurst

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Intensive Care Foundation

Address [1]

Level 2, 10 Ievers Terrace
Carlton, Victoria, 3053
Australia

Country [1]

Australia

Primary sponsor type

Hospital

Name

University Hospital Geelong

Address

Ryrie St
Geelong, 3220
VIC

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

University

Name [1]

Australian and New Zealand Intensive Care Research Centre, Department of Epdiemiology and Preventive Medicine, Monash University

Address [1]

Level 3
533 St Kilda Rd
Melbourne
VIC 3004

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Barwon Health REGI

Ethics committee address [1]

PO Box 281
Geelong
VIC 3220

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

21/03/2017

Approval date [1]

27/02/2018

Ethics approval number [1]

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 limited experience in using 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. Bisphosphonates, like Zoledronic Acid, have been used to treat critically ill patients with biochemical evidence of bone resorption, and shown to be associated with reduced mortality in retrospective studies of critically ill patients. 

Denosumab and Zolderonic Acid have side effects, including acute hypocalcaemia, flu like symptoms, osteonecrosis of the jaw, real impairment (zoledronic acid), change in  immune function (denosumab), and post cessation bone loss (denosumab). Given these we plan to delay study drug administration until there is no active infection, and stable renal function. 

At the completion of this study we will examine the safety and effect of denosumab and zoledronic acid 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 effect on bone mass, fractures, and survival.

Trial website

Trial related presentations / publications

Public notes

Attachments [1]

/AnzctrAttachments/372599-SofterRCTpilotv4_2103017.pdf (Protocol)

Contacts

Principal investigator

Name

A/Prof Neil Orford

Address

Intensive Care Unit
Level 4
University Hospital Geelong
Ryrie St
Geelong
VIC 3220

Country

Australia

Phone

+61342151722

Fax

+61342151761

[email protected]

Contact person for public queries

Name

Rosemary Finnemore

Address

Intensive Care Unit
Level 4
University Hospital Geelong
Ryrie St
Geelong
VIC 3220

Country

Australia

Phone

+61342151761

Fax

+61342151761

[email protected]

Contact person for scientific queries

Name

Neil Orford

Address

Intensive Care Unit
Level 4
University Hospital Geelong
Ryrie St
Geelong
VIC 3220

Country

Australia

Phone

+61342151761

Fax

+61342151761

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

Pilot feasibility study, IPD not included in protocol design

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
4220	Study protocol			[email protected]		372599-(Uploaded-21-08-2019-14-30-02)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	A pilot feasibility randomised controlled trial of bone antiresorptive agents on bone turnover markers in critically ill women.	2024	https://dx.doi.org/10.1038/s41598-024-52607-1

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically