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Trial registered on ANZCTR


Registration number
ACTRN12610000507088
Ethics application status
Approved
Date submitted
15/06/2010
Date registered
18/06/2010
Date last updated
5/12/2019
Date data sharing statement initially provided
5/12/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Clinical trial of zoledronic acid in children and adolescents with Duchenne muscular dystrophy
Scientific title
Open label, randomized clinical trial of zoledronic acid (Aclasta) versus vitamin D plus calcium in children and adolescents with Duchenne muscular dystrophy, to assess change in lumbar spine bone density over 12 months
Secondary ID [1] 252027 0
nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Duchenne muscular dystrophy 257572 0
osteopaenia 257576 0
Condition category
Condition code
Neurological 257739 257739 0 0
Other neurological disorders
Musculoskeletal 257740 257740 0 0
Osteoporosis
Human Genetics and Inherited Disorders 257747 257747 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
to assess whether zoledronic acid 0.025mg/kg/dose as an intravenous preparation infused over 30 minutes, at 0,3 months then 0.05mg/kg/dose at 6,12 and 18 months is superior to calcium as an oral tablet plus vitamin D as orally administered capsule, to improve bone density and reduce fracture risk in boys with Duchenne muscular dystrophy
Intervention code [1] 256665 0
Prevention
Intervention code [2] 256670 0
Treatment: Drugs
Comparator / control treatment
Boys with Duchenne Muscular Dystrophy aged 6-16 years on just calcium 1000mg oral tablets daily and vitamin D 800IU oral tablets daily for 24 months
Control group
Active

Outcomes
Primary outcome [1] 258622 0
Change in lumbar spine (LS) areal bone mineral density (aBMD) Z-score as assessed by dual Xray absorptiometry (DEXA), with volumetric calculation for each subject to account for size variability [Bone mineral apparent density (BMAD)].
Timepoint [1] 258622 0
0,12 and 24 months
Secondary outcome [1] 264557 0
Between-treatment differences for the change from baseline in Lumbar Spine(LS) areal BMD Z-score, LS and total body Bone Mineral Content(BMC) assessed by DEXA and in bone turnover markers assessed by alkaline phosphatase,urine deoxypyridinoline cross links
Timepoint [1] 264557 0
0, 12 and 24 months
Secondary outcome [2] 264558 0
Between-treatment differences for the change from baseline in tibial metaphyseal BMC and volumetric BMD(vBMD), and diaphyseal BMC, vBMD and cross-sectional area on peruipheral Quantitative Computed Tomography(pQCT)
Timepoint [2] 264558 0
0, 12 and 24 months
Secondary outcome [3] 264559 0
Between-treatment differences for the proportion of patients with new vertebral fractures and vertebral morphometry relative to baseline using vertebral Xrays to be assessed by clinician blinded to the type of intervention
Timepoint [3] 264559 0
0, 12 and 24 months
Secondary outcome [4] 264563 0
Between-treatment differences for the number of patients with new clinical fractures relative to baseline as assessed by history of overt long bone fracture and by vertebral Xrays
Timepoint [4] 264563 0
0, 12 and 24 months
Secondary outcome [5] 307059 0
change from baseline in pain scores using the WONG BAKER pain faces scale where the children rate their pain from 0 to 10 using pictures of emotional faces as a guide
Timepoint [5] 307059 0
0, 12 and 24 months
Secondary outcome [6] 307060 0
Change from baseline in walking ability assessed by the six minute walk test which measures how far a child can walk in six minutes.
Timepoint [6] 307060 0
baseline, 12 and 24 months

Eligibility
Key inclusion criteria
All boys between 6-16 years with confirmed Duchenne Muscular Dystrophy (DMD) and who are receiving glucocorticoid therapy (this is universally prednisolone)
Minimum age
6 Years
Maximum age
16 Years
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
Genant Grade 3 or greater vertebral compression
1. Any prior use of osteoporosis or bone-modifying therapy, such as bisphosphonates, sodium fluoride, calcitonin, calcitriol, Gonadotrophin releasing hormone agonists or Growth Hormone (GH).
2. Patients who have received testosterone therapy may only be included in the trial if this therapy was given as part of physiological replacement in the setting of documented hormonal deficiencies
3. Any prior history of malignancy
4. Any medical condition that might interfere with the evaluation of LS BMD, such as severe scoliosis or spinal fusion. Patients with less than 3 evaluable vertebrae by DEXA evaluation in the region of interest (ROI) L1-L4, as confirmed by the central imaging laboratory, will not be considered eligible for this study.
5. Hypocalcemia and hypophosphatemia: any value (age-matched) below the normal range at screening
6. Vitamin D deficiency (serum 25-hydroxy vitamin D concentrations of < 50 nmol/L) at screening
7. Renal impairment: Glomerulr filtration rate (GFR) < 35 ml/min/1.73 m2 at screening based on the Schwartz formula.
8. A serum creatinine increase between Visit 1 and Visit 2 greater than 44.2 mmol/L
9. History of hyperparathyroidism, hypothyriodism or hyperthyroidism within 1 year of screening
10.History of sarcoidosis, primary bone disease (osteogenesis imperfecta, idiopathic juvenile
osteoporosis, rickets/osteomalacia)., Kawasaki’s disease or Henoch-Schonlein Purpura.
11. Diagnosis of active uveitis (symptomatic or asymptomatic) at the time of enrollment of the study.
12. Any subject involved in another study, if an investigational agent is deemed by investigators to possible interfere with this study agent. ( for example use of a different bisphosphonate or a statin, a drug that utilizes the same biochemical pathways )

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)
Randomisation will be achieved using minimisation (a highly efficient method accounting for strataespecially when the sample sizes are small), with strata being treating centre and age (young: 4- 8yrs ,older: 9-13 and 14-18). Such stratification will group changes in bone quality due in part to pubertal status- pre, peri and post pubertal. . This, together with minimisation will ensure allocation concealment for the study
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be achieved via a web based system from the National Health and Medical Research Council (NHMRC) Clinical Trials Centre
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/09/2010
Actual
11/05/2012
Date of last participant enrolment
Anticipated
31/12/2016
Actual
6/07/2017
Date of last data collection
Anticipated
Actual
3/07/2019
Sample size
Target
60
Accrual to date
Final
62
Recruitment in Australia
Recruitment state(s)
NSW,WA,VIC
Recruitment hospital [1] 2149 0
Princess Margaret Hospital - Subiaco
Recruitment hospital [2] 2150 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [3] 2151 0
Sydney Children's Hospital - Randwick
Recruitment hospital [4] 2152 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 3002 0
3052
Recruitment outside Australia
Country [1] 5854 0
New Zealand
State/province [1] 5854 0
Auckland

Funding & Sponsors
Funding source category [1] 257137 0
Commercial sector/Industry
Name [1] 257137 0
Novartis
Country [1] 257137 0
Australia
Funding source category [2] 257138 0
Charities/Societies/Foundations
Name [2] 257138 0
Altum
Country [2] 257138 0
United States of America
Primary sponsor type
Hospital
Name
Royal Children's Hospital
Address
Flemington Rd
Parkville
Victoria 3052
Country
Australia
Secondary sponsor category [1] 256402 0
Hospital
Name [1] 256402 0
The Children's hospital at Westmead
Address [1] 256402 0
Locked Bag 4001, Westmead 2145. Street address: Cnr Hawkesbury Rd and Hainsworth St, Westmead, Sydney, N.S.W.
Country [1] 256402 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259176 0
Royal Children's hospital
Ethics committee address [1] 259176 0
Flemington Rd
Parkville
Victoria 3052
Ethics committee country [1] 259176 0
Australia
Date submitted for ethics approval [1] 259176 0
08/02/2010
Approval date [1] 259176 0
01/07/2010
Ethics approval number [1] 259176 0
29124A
Ethics committee name [2] 290643 0
princess margaret hospital
Ethics committee address [2] 290643 0
roberts rd subiaco, Perth WA 6008
Ethics committee country [2] 290643 0
Australia
Date submitted for ethics approval [2] 290643 0
Approval date [2] 290643 0
23/07/2013
Ethics approval number [2] 290643 0
2013018
Ethics committee name [3] 290644 0
sydney children's hospital network
Ethics committee address [3] 290644 0
Level 2, High Street
Randwick NSW 2031

AND

Cnr Hawkesbury Road and Hainsworth Street, Westmead
Locked Bag 4001, Westmead NSW 2145
Ethics committee country [3] 290644 0
Australia
Date submitted for ethics approval [3] 290644 0
Approval date [3] 290644 0
11/02/2014
Ethics approval number [3] 290644 0
11/CHW/26
Ethics committee name [4] 292642 0
Health and Disability ethics committees
Ethics committee address [4] 292642 0
Ministry of Health
C/- MEDSAFE, Level 6, Deloitte House
10 Brandon Street
PO Box 5013
Wellington
6011
Ethics committee country [4] 292642 0
New Zealand
Date submitted for ethics approval [4] 292642 0
Approval date [4] 292642 0
10/03/2014
Ethics approval number [4] 292642 0
13/NTB/147

Summary
Brief summary
Boys with Duchenne muscular dystrophy (DMD) have an increased risk of long bone and vertebral fracture due to reduced bone mass (osteopenia). In DMD, osteopenia is due to both reduced mobility and glucocorticoid use. There is no recognised treatment for osteopenia in DMD. Bisphosphonates are a class of drug which act primarily by decreasing the activity of the bone resorbing cells, the osteoclast. In children with osteogenesis imperfecta (brittle bone disease) bisphosphonates have been shown to improve bone strength and increase bone density (areal Bone Mineral Density (aBMD)) through a combination of increased cortical thickness and trabecular number.
Bisphosphonates alter the course of corticosteroid induced bone loss and largely prevent this complication in the adult population. It is more difficult to provide such evidence in a paediatric population where linear growth and puberty both rapidly alter skeletal size and make interpretation of bone density more difficult. With techniques of volumetric bone density (BMAD) calculation available, more accurate data can now be observed.
Study significance
This study is powered to provide definitive data on the utility of 3-6 monthly intravenous zoledronic acid to improve bone density in boys with DMD. Results from this study will be used to develop a study to assess fracture reduction in this population. This in turn would have far reaching consequences in terms of potential reduction in morbidity, hospitalization and immobilization of affected boys.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 31293 0
Prof Margaret Zacharin
Address 31293 0
Dept of Endocrinology Royal Children's hospital Flemington Rd Parkville Victoria 3052
Country 31293 0
Australia
Phone 31293 0
+61393455951
Fax 31293 0
+61393477763
Email 31293 0
[email protected]
Contact person for public queries
Name 14540 0
Margaret Zacharin
Address 14540 0
Dept of Endocrinology
Royal Children's hospital
Flemington Rd
Parkville
Victoria 3052
Country 14540 0
Australia
Phone 14540 0
+61393455951
Fax 14540 0
+61393477763
Email 14540 0
[email protected]
Contact person for scientific queries
Name 5468 0
Margaret Zacharin
Address 5468 0
Dept of Endocrinology
Royal Children's hospital
Flemington Rd
Parkville
Victoria 3052
Country 5468 0
Australia
Phone 5468 0
+61393455951
Fax 5468 0
+61393477763
Email 5468 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
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
SourceTitleYear of PublicationDOI
EmbaseRandomized Controlled Trial Evaluating the Use of Zoledronic Acid in Duchenne Muscular Dystrophy.2021https://dx.doi.org/10.1210/clinem/dgab302
N.B. These documents automatically identified may not have been verified by the study sponsor.