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Trial registered on ANZCTR


Registration number
ACTRN12616001051437
Ethics application status
Approved
Date submitted
2/08/2016
Date registered
5/08/2016
Date last updated
4/06/2019
Date data sharing statement initially provided
21/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised, double-blind, placebo controlled trial to examine the effects of total oestradiol depletion on bone microstructure and the efficacy of denosumab in preventing microstructural bone decay in premenopausal women with early breast cancer
Scientific title
Efficacy study to evaluate denosumab compared to placebo in preventing microstructural bone decay in premenopausal women receiving total oestradiol depletion therapy for early breast cancer
Secondary ID [1] 289799 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
premenopausal osteoporosis 299704 0
breast cancer 299768 0
Condition category
Condition code
Metabolic and Endocrine 299642 299642 0 0
Other endocrine disorders
Cancer 299702 299702 0 0
Breast
Musculoskeletal 299703 299703 0 0
Osteoporosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Denosumab 60mg subcutaneous injection at 6-month intervals for a 12-month study duration administered by trial investigator.
Intervention code [1] 295470 0
Treatment: Drugs
Comparator / control treatment
Placebo - normal saline subcutaneous injection at 6-month intervals for a 12-month study duration administered by trial investigator.
Control group
Placebo

Outcomes
Primary outcome [1] 299109 0
total volumetric BMD at the distal tibia measured using high-resolution peripheral quantitative computed tomography
Timepoint [1] 299109 0
12 months from baseline
Secondary outcome [1] 326210 0
areal bone mineral density (lumbar spine, femoral neck, hip and non-dominant distal radius) as measured by dual energy X-ray absorptiometry (DEXA)
Timepoint [1] 326210 0
6 and 12 months from baseline
Secondary outcome [2] 326211 0
bone remodeling markers (beta carboxy-terminal type I collagen telopeptide (CTX) and procollagen type 1 amino-terminal propeptide (P1NP) by serum assay
Timepoint [2] 326211 0
6 and 12 months from baseline
Secondary outcome [3] 326212 0
lean mass measured by DEXA
Timepoint [3] 326212 0
6 and 12 months from baseline
Secondary outcome [4] 326213 0
homeostatic model assessment of insulin resistance derived from measurement of fasting plasma glucose and fasting serum insulin.
Timepoint [4] 326213 0
6 and 12 months from baseline
Secondary outcome [5] 326214 0
lipid levels by serum assay
Timepoint [5] 326214 0
6 and 12 months from baseline
Secondary outcome [6] 326215 0
quality of life assessed using validated questionnaires (MENQOL and FACT-B/ES)
Timepoint [6] 326215 0
6 and 12 months from baseline
Secondary outcome [7] 326365 0
visceral fat volume and distribution measured by DEXA
Timepoint [7] 326365 0
6 and 12 months from baseline
Secondary outcome [8] 326366 0
subcutaneous fat volume and distribution measured by DEXA
Timepoint [8] 326366 0
6 and 12 months from baseline
Secondary outcome [9] 365218 0
total volumetric BMD at the distal radius measured using high-resolution peripheral quantitative computed tomography
Timepoint [9] 365218 0
6 and 12 months from baseline
Secondary outcome [10] 365219 0
cortical volumetric BMD at the distal radius and distal tibia measured using high resolution peripheral quantitative computed tomography
Timepoint [10] 365219 0
6 and 12 months from baseline
Secondary outcome [11] 365220 0
trabecular volumetric BMD at the distal radius and distal tibia measured using high resolution peripheral quantitative computed tomography
Timepoint [11] 365220 0
6 and 12 months from baseline
Secondary outcome [12] 365221 0
cortical porosity at the distal radius and distal tibia measured using high resolution peripheral quantitative computed tomography
Timepoint [12] 365221 0
6 and 12 months from baseline
Secondary outcome [13] 365222 0
Trabecular number, thickness and separation at the distal radius and distal tibia measured using high resolution peripheral quantitative computed tomography
Timepoint [13] 365222 0
6 and 12 months from baseline
Secondary outcome [14] 365223 0
Matrix mineral density at the distal radius and distal tibia measured using high resolution peripheral quantitative computed tomography
Timepoint [14] 365223 0
6 and 12 months from baseline

Eligibility
Key inclusion criteria
- Premenopausal women with oestrogen-receptor positive, non-metastatic breast cancer (TxNxM0) based on documented pathological and radiological evaluation. Menopausal status will be defined clinically at the diagnosis of breast cancer.

Premenopausal: a regular cycle in the last 3 months prior to diagnosis of breast cancer
Perimenopausal: absent cycles for 3-12 months
Postmenopausal: absent cycles for 12 months or more

- About to commence treatment with ovarian suppression with a view to subsequent aromatase inhibition as determined by the treating oncologist

- Endocrine therapy intended for at least 12 months

- Eastern Cooperative Oncology Group (ECOG) 0 and 1

- Able to personally read and understand the Participant Information and Consent Form and provide written, signed and dated informed consent to participate in the study

- Able and willing to meet all protocol-required procedures and visits
Minimum age
18 Years
Maximum age
55 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- Bone mineral density T-score at the lumbar spine/hip/femoral neck <-2.0SD

- Pre-existing minimal trauma fractures (excluding fractures of fingers, toes, hands, feet and skull)

Current evidence or prior history of any of the following:

- Metabolic bone disorder(s)

- Drugs for treatment of bone-related disorders

- Prolonged glucocorticoid use for 2 or more weeks continuously in the past 6 months

- Significant inflammatory or malabsorptive condition(s)

- Osteonecrosis or osteomyelitis of the jaw

- Atypical femoral fracture(s)

- Diabetes mellitus

- History of any solid organ or bone marrow transplant

- Malignancy within the last 5 years (except breast cancer and non-melanoma skin cancers)

Abnormalities of the following per central laboratory reference ranges:

- Hypo/hypercalcaemia

- Hypo/hyperparathyroidism

- Renal impairment (eGFR <45ml/min/1.73m2)

- 25-hydroxy vitamin D deficiency (<12nmol/L). Repletion will be allowed and participants may be re-screened.

- Self-reported recreational drug use or alcohol dependence within 12 months prior to screening

- Pregnancy

- History or evidence of any other clinically significant disorder, condition or disease that in the opinion of the study investigator would pose a risk to participant safety or interfere with the study evaluation, procedures or completion

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)
Randomised

Central randomisation by the Austin Health clinical trials pharmacy, supervised by the senior clinical trials pharmacist. Dispensing pharmacists, trial investigators (who will responsible for administration of the drug/placebo) and participants will be blinded to intervention allocation.
Methods used to generate the sequence in which subjects will be randomised (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
1:1 allocation
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis

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] 6320 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 13855 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 294184 0
University
Name [1] 294184 0
University of Melbourne
Address [1] 294184 0
University of Melbourne - Austin Health
145 Studley Road, Heidelberg, Victoria 3084, Australia
Country [1] 294184 0
Australia
Primary sponsor type
Individual
Name
Associate Professor Mathis Grossmann
Address
University of Melbourne - Austin Health
Level 7 Lance Townsend Building, Austin Health, 145 Studley Road, Heidelberg, Victoria, 3084, Australia
Country
Australia
Secondary sponsor category [1] 293010 0
None
Name [1] 293010 0
NA
Address [1] 293010 0
NA
Country [1] 293010 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295585 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 295585 0
Austin Health
145 Studley Road
Heidelberg
Victoria 3084
Ethics committee country [1] 295585 0
Australia
Date submitted for ethics approval [1] 295585 0
05/04/2016
Approval date [1] 295585 0
26/08/2016
Ethics approval number [1] 295585 0
HREC Reference Number: HREC/16/Austin/136

Summary
Brief summary
The primary purpose of this study is to compare the efficacy of denosumab treatment with placebo in preventing bone decay in premenopausal women being treated with ovarian suppression and aromatase inhibition for breast cancer.

Who is it for?
You may be eligible to enrol in this trial if you are a premenopausal woman aged 18 to 55 who has been diagnosed with oestrogen-receptor positive, non-metastatic breast cancer (TxNxM0) for which you are scheduled to begin ovarian suppression and aromatase inhibition therapy which is intended to last for at least 12 months.

Study details
All participants enrolled in this trial will be randomly allocated (by chance) to receive either denosumab once every 6 months by subcutaneous injection or to receive placebo once every 6 months for a 12-month study period.

Participants will be followed-up at 6 and 12 months after starting the trial drug/placebo with scans, blood tests and questionnaires which will be used to measure bone density and structure, body composition, blood markers of bone health and cardiovascular risk and quality of life.

It is hoped that the findings from this trial will provide information on the extent of bone decay which occurs as a result of ovarian suppression and aromatase inhibition therapy, and the efficacy of denosumab in preventing this decay in premenopausal women with oestrogen-receptor positive breast cancer.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67850 0
A/Prof Mathis Grossmann
Address 67850 0
Level 7 Lance Townsend Building, Austin Health, 145 Studley Road, Heidelberg, Victoria 3084, Australia
Country 67850 0
Australia
Phone 67850 0
+61394965000
Fax 67850 0
Email 67850 0
mathisg@unimelb.edu.au
Contact person for public queries
Name 67851 0
Dr Sabashini Ramchand
Address 67851 0
Austin Health, 145 Studley Road, Heidelberg, Victoria 3084, Australia
Country 67851 0
Australia
Phone 67851 0
+61478168578
Fax 67851 0
Email 67851 0
sabashini.ramchand@austin.org.au
Contact person for scientific queries
Name 67852 0
Dr Sabashini Ramchand
Address 67852 0
Austin Health, 145 Studley Road, Heidelberg, Victoria 3084, Australia
Country 67852 0
Australia
Phone 67852 0
+61478168578
Fax 67852 0
Email 67852 0
sabashini.ramchand@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
to be confirmed
What supporting documents are/will be available?
Informed consent form
How or where can supporting documents be obtained?
Type [1] 886 0
Informed consent form
Citation [1] 886 0
Link [1] 886 0
Email [1] 886 0
Other [1] 886 0
Summary results
No Results