Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000141640p
Ethics application status
Not yet submitted
Date submitted
26/01/2023
Date registered
10/02/2023
Date last updated
10/02/2023
Date data sharing statement initially provided
10/02/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating the effect of Romosozumab on osteoporosis following spinal cord injury
Scientific title
Investigating the effect of Romosozumab on osteoporosis following spinal cord injury
Secondary ID [1] 308837 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Osteoporosis 328796 0
Acute Spinal Cord Injury 328797 0
Condition category
Condition code
Musculoskeletal 325806 325806 0 0
Osteoporosis
Physical Medicine / Rehabilitation 325807 325807 0 0
Other physical medicine / rehabilitation
Neurological 325885 325885 0 0
Other neurological disorders
Injuries and Accidents 325886 325886 0 0
Fractures

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a randomised open-label trial which aims to determine the effects of monthly romosozumab 210 mg administered subcutaneously for 12 months followed by zoledronic acid 5 mg administered intravenously at year 1, 3 and 5 on bone mineral density (BMD), fractures, and biochemical markers of bone formation and resorption, in patients with spinal cord injury.
Romosuzumab will be self-administered or administered by a formal or informal carer. Zoledronic acid will be administered by a registered nurse.
Adherence will be monitored through assessment, participant diary and self-reported adherence, pharmacy dispensing, study records and attendance.
Intervention code [1] 325280 0
Treatment: Drugs
Intervention code [2] 325281 0
Prevention
Comparator / control treatment
Zoledronic acid 5mg intravenously, administered at baseline, year 1, 3 and 5. Zoledronic acid will be administered by a registered nurse.
Adherence will be monitored through assessment, participant diary and self-reported adherence, pharmacy dispensing, study records and attendance.

Adult patients with an acute SCI admitted to the Princess Alexandra Hospital with an American Spinal Injury Association (ASIA) Impairment Scale A-C from 1 January 2013 - study completion will be included as a non-treated historical control group to assess the impact of combined romosozumab and zoledronic acid, zoledronic acid alone and no treatment on the incidence of osteoporosis and fractures post-SCI. Data will be obtained from patient medical records.
Control group
Active

Outcomes
Primary outcome [1] 333648 0
Total BMD change at the knee (distal femur) as assessed by Dual-energy X-ray absorptiometry (DXA)
Timepoint [1] 333648 0
Assessed at baseline and at 12 months post-randomisation
Primary outcome [2] 333649 0
Total BMD change at the knee (proximal tibia) as assessed by Dual-energy X-ray absorptiometry (DXA)
Timepoint [2] 333649 0
Assessed at baseline and at 12 months post-randomisation
Secondary outcome [1] 417854 0
Change in BMD at the distal femur as assessed by Dual-energy X-ray absorptiometry (DXA)
Timepoint [1] 417854 0
Assessed at baseline and at 1, 3, 5, 7 and 10 years post-randomisation
Secondary outcome [2] 418049 0
Change in BMD at the proximal tibia as assessed by Dual-energy X-ray absorptiometry (DXA)
Timepoint [2] 418049 0
Assessed at baseline and at 1, 3, 5, 7 and 10 years post-randomisation
Secondary outcome [3] 418050 0
Change in BMD at the total hip as assessed by Dual-energy X-ray absorptiometry (DXA)
Timepoint [3] 418050 0
Assessed at baseline and at 1, 3, 5, 7 and 10 years post-randomisation
Secondary outcome [4] 418051 0
Change in BMD at the femoral neck as assessed by Dual-energy X-ray absorptiometry (DXA)
Timepoint [4] 418051 0
Assessed at baseline and at 1, 3, 5, 7 and 10 years post-randomisation
Secondary outcome [5] 418052 0
Change in BMD at the lumbar spine as assessed by Dual-energy X-ray absorptiometry (DXA)
Timepoint [5] 418052 0
Assessed at baseline and at 1, 3, 5, 7 and 10 years post-randomisation
Secondary outcome [6] 418053 0
Change in bone specific alkaline phosphatase (bsALP)
Timepoint [6] 418053 0
Assessed at baseline and at 6 months, 1, 3, 5, 7 and 10 years post-randomisation
Secondary outcome [7] 418054 0
Change in Procollagen 1 Intact N-Terminal Propeptide (P1NP)
Timepoint [7] 418054 0
Assessed at baseline and at 6 months, 1, 3, 5, 7 and 10 years post-randomisation
Secondary outcome [8] 418055 0
Change in C-terminal telopeptide of type 1 collagen (CTX)
Timepoint [8] 418055 0
Assessed at baseline and at 6 months, 1, 3, 5, 7 and 10 years post-randomisation
Secondary outcome [9] 418056 0
Change in osteocalcin
Timepoint [9] 418056 0
Assessed at baseline and at 6 months, 1, 3, 5, 7 and 10 years post-randomisation
Secondary outcome [10] 418057 0
Quality of life as assessed by the Spinal Cord Injury – Quality of Life (SCI-QOL) measurement system
Timepoint [10] 418057 0
Assessed at baseline and at 1, 3, 5, 7 and 10 years post-randomisation
Secondary outcome [11] 418060 0
Fractures as determined by imaging including x-ray or computerized tomography (CT) scan, medical records, reported by participants.
Timepoint [11] 418060 0
Assessed at baseline and at 1, 3, 5, 7 and 10 years post-randomisation

Eligibility
Key inclusion criteria
- Adults aged 18 years to 65 years (upper age limit is to reduce the influence of age on ability of the skeleton to respond to pharmacologic stimulation and reduce the risk of losing participants to follow-up)
- Within 3 months of acute SCI
- American Spinal Injury Association (ASIA) Impairment Scale A-C
- People with SCI and traumatic brain injury will be included if they are able to provide informed consent
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Unable or unwilling to provide informed written consent or comply with follow-up and study protocol
- History of prior bone disease (i.e. Paget’s disease, primary hyperparathyroidism, current or previously treated osteoporosis)
- Documented heterotopic ossification (HO)
- Endocrinopathies (including untreated hyperthyroidism, active Cushing’s Syndrome, hypocalcaemia)
- Severe underlying chronic disease (including COPD, end-stage cardiac failure, chronic kidney (glomerular filtration rate <35ml/min) or liver failure (liver function tests >twice upper limit of normal)
- Chronic alcohol abuse
- Pregnancy, or planning pregnancy or breastfeeding
- Current diagnosis of cancer, including osteosarcoma
- Myocardial infarction or stroke within the preceding year and/or high cardiovascular risk, 10 years Framingham score >20%
- Life expectancy less than 5 years

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation not concealed
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).
Participants will be matched for age, time since injury (<1-month post injury or 2-3 months post-injury), ASIA Impairment Scale, gender and menstrual status if female.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
An historical untreated control group who had received care at the Princess Alexandra Hospital but had not received pharmacological treatment for prevention of osteoporosis will be used as a comparator group in terms of incidence of fractures. Participants will be matched to historical controls in terms of age, sex and injury level.
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
At 12 months after acute SCI, the loss of BMD at the knee (distal femur and proximal tibia) is approximately 20%. No bone-preserving effect at the knee has been observed with the administration of zoledronic acid. To date, no studies have reported the effect of initiating treatment with romosozumab on sublesional bone in the subacute period after SCI. It is predicted that romosozumab will inhibit sclerostin mediated bone loss, and therefore we have conservatively estimated a 0% change in BMD at 12 months at the knee. Therefore, the study would need 13 in each group to achieve alpha of 0.05 and beta of 0.8 to show a 20% difference in knee BMD between romosozumab and zoledronic acid-treated patients. To account for approximately 10% dropout, the target recruitment is 30 participants (15 in each group).

Continuous variables will be expressed as mean ± SEM or median (interquartile range) as appropriate and categorical variables will be reported as number and percentage. Continuous variables will be analysed using unpaired t-test or Mann Whitney U test depending on whether data satisfy parametric assumptions. Categorical variables will be analysed using chi-squared or Fisher’s exact test as appropriate. The relationships between continuous variables will be assessed using Pearson correlation and regression analysis or Spearman's rank-order correlation. Percent change variables in each group will be compared between the treatment groups by independent t tests. For BMD, unpaired t tests with Bonferroni correction will be applied to side-to-side comparisons for skeletal regions of interest. Assuming no significant difference will be found between the left and right sides, they will be averaged and presented as a single value for each region. Changes in outcome measures will be compared between treatments over time using repeated-measures ANOVA. Adverse event rates will be compared using Chi-Square tests. A two-tailed P < 0.05 is considered statistically significant.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/04/2023
Actual
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
31/12/2034
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 23883 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 39347 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 313062 0
Hospital
Name [1] 313062 0
Princess Alexandra Hospital
Country [1] 313062 0
Australia
Primary sponsor type
Hospital
Name
Princess Alexandra Hospital, Metro South Health
Address
199 Ipswich Road, Woolloongabba, QLD, 4102
Country
Australia
Secondary sponsor category [1] 314751 0
None
Name [1] 314751 0
Address [1] 314751 0
Country [1] 314751 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 312313 0
Metro South Research Ethics Committee
Ethics committee address [1] 312313 0
199 Ipswich Road, Woolloongabba, QLD, 4102
Ethics committee country [1] 312313 0
Australia
Date submitted for ethics approval [1] 312313 0
16/02/2023
Approval date [1] 312313 0
Ethics approval number [1] 312313 0

Summary
Brief summary
Spinal cord injury (SCI) is associated with severe rapid bone loss below the level of injury, and subsequently osteoporosis and increased risk of minimal trauma fractures. There is currently no effective treatment for treating SCI-induced osteoporosis. Current methods of prevention, predominantly bisphosphonates, have very limited efficacy. Sclerostin is now known to mediate SCI-induced bone loss. Recently, a sclerostin inhibitor, romosozumab, has become available for the treatment of osteoporosis. Sclerostin inhibition prevents bone loss following SCI in pre-clinical studies. We hypothesis that romosozumab will be highly effective for the prevention of bone loss and osteoporosis in SCI. This study will compare romosozumab followed by the bisphosphonate, zoledronic acid versus zoledronic acid alone, administered early after acute SCI, for prevention of SCI-induced osteoporosis. We will recruit 30 participants (15 in each group) in a randomised controlled study. Participants will either receive romosozumab for 12 months followed by maintenance therapy with zoledronic acid, or zoledronic acid alone. We expect to show that the marked bone loss which occurs following acute SCI can be prevented by the administration of romosozumab.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124210 0
Dr Emily Brooks
Address 124210 0
Department of Diabetes and Endocrinology
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba, QLD, 4102
Country 124210 0
Australia
Phone 124210 0
+61 0731769562
Fax 124210 0
Email 124210 0
emily.brooks@health.qld.gov.au
Contact person for public queries
Name 124211 0
Dr Emily Brooks
Address 124211 0
Department of Diabetes and Endocrinology
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba, QLD, 4102
Country 124211 0
Australia
Phone 124211 0
+61 0731761111
Fax 124211 0
Email 124211 0
emily.brooks@health.qld.gov.au
Contact person for scientific queries
Name 124212 0
Dr Emily Brooks
Address 124212 0
Department of Diabetes and Endocrinology
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba, QLD, 4102
Country 124212 0
Australia
Phone 124212 0
+61 0731761111
Fax 124212 0
Email 124212 0
emily.brooks@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.

Documents added automatically
No additional documents have been identified.