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Trial registered on ANZCTR


Registration number
ACTRN12610000281099
Ethics application status
Approved
Date submitted
31/03/2010
Date registered
8/04/2010
Date last updated
23/05/2011
Type of registration
Retrospectively registered

Titles & IDs
Public title
The efficacy and safety of zoledronate in children and adolescents with chronic neurological conditions and osteoporosis: a crossover trial with long term follow up.
Scientific title
The efficacy and safety of zoledronate in children and adolescents with chronic neurological conditions and osteoporosis: a crossover trial with long term follow up.
Secondary ID [1] 1569 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Osteoporosis 257078 0
Condition category
Condition code
Metabolic and Endocrine 257233 257233 0 0
Other metabolic disorders
Musculoskeletal 257238 257238 0 0
Osteoporosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Calcium 600mg oral tablet daily for 6 months
Vitamin D 400 IU oral solution daily for 6 months
Calcium and Vitamin D supplementation will be started at baseline and continued throughout the study.

There is no wash out period.

At 6 months and 18 months patient will recieve intravenous Zoledronate. The dose will be 0.05mg/kg with a maximum dose of 2mg.
The calculated dose of reconstituted zoledronate will be diluted in 50ml of Normal Saline and infused over 30 minutes.
Intervention code [1] 256252 0
Treatment: Drugs
Comparator / control treatment
Cross over trial.
Control group
Active

Outcomes
Primary outcome [1] 258123 0
Efficacy of zoledronate:
The efficacy of zoledronate will be assessed by the improvement in the participants bone mineral density (BMD) z score over time.
Timepoint [1] 258123 0
Time = 0
Time = 6 months
Time = 12 months
Time = 18 months
Time = 24 months
Time = 30 months
Primary outcome [2] 258134 0
Fracture rate
Number of new fractures during the study period will be collected. Fracture will be diagnosed via x-ray.
Timepoint [2] 258134 0
Time = 0
Time = 6 months
Time = 12 months
Time = 18 months
Time = 24 months
Time = 30 months
Primary outcome [3] 258135 0
Biochemical measures
Serum parathyroid hormone (PTH)
Urinary N-telopeptides
Timepoint [3] 258135 0
Time = 0
Time = 6 months
Time = 12 months
Time = 18 months
Time = 24 months
Time = 30 months
Secondary outcome [1] 263771 0
Safety of zoledronate
Comparing rate of adverse events in the 6 months following zoledronate infusion with that in the 6 months prior to the infusion.

Due to the higher doses and potency, intravenous bisphosphonates have a greater potential for side effects than oral agents, including nephrotoxicity, osteonecrosis of the jaw, hypocalcemia, and post infusion pyrexia and flu-like symptoms.

The most common adverse event associated with intravenous bisphosphonate use is flu like symptoms (including pyrexia and myalgia), but this is usually short lived, self limiting, mild in intensity, and normally occurs only after the first dose. These acute phase symptoms can be minimized by the administration of ibuprofen or prednisolone, and, if symptoms are very severe, with prednisolone.

Hypocalcemia after intravenous bisphosphonate administration occurs secondary to increased rates of osteoclast-mediated bone resorption. This is well recognised and management protocols are available to treat this complication with calcium and vitamin D supplementation.

We will ask about adverse events at 6 monthly reviews.
Timepoint [1] 263771 0
Time = 0
Time = 6 months
Time = 12 months
Time = 18 months
Time = 24 months
Time = 30 months
Secondary outcome [2] 263772 0
Acceptability of zoledronate
1. Comparing rate of recruitment refusal with that observed for the pamidronate trial and
2. Comparing rate of withdrawal or re-infusion refusal with that observed in the pamidronate trial.

We will document the number of refusals and withdrawals from the study.
Timepoint [2] 263772 0
Time = 0
Time = 6 months
Time = 12 months
Time = 18 months
Time = 24 months
Time = 30 months
Secondary outcome [3] 263773 0
efficacy of zoledronate
1. Incidence of new fractures during the study.
2. Change in bone metabolism parameters, such as alkaline phosphatase, parathyroid hormone, bone specific alkaline phosphatase, and urine type I collagen N-telopeptide (NTX).
c. long term changes in bone mineral density (BMD) at 12 and 24 months following zoledronate infusion
d. perception of musculoskeletal pain as determined by Brief Pain Inventory (BPI).
e. Quality of Life (QOL) as determined by PedsQL (Paediatric QOL questionnaire).
f. linear growth - height and weight are documented 6 monthly.
Timepoint [3] 263773 0
Time = 0
Time = 6 months
Time = 12 months
Time = 18 months
Time = 24 months
Time = 30 months

Eligibility
Key inclusion criteria
Children and adolescents eligible to participate in the study must be:
1. Diagnosed with a chronic neurological condition.
2. Aged = 4 years to < 18, inclusive
3. Have an increased risk of fractures as defined by BMD <-2.5 at one or more sites and, a history of at least one radiologically confirmed, non traumatic or low impact fracture and/or significant bone pain (as determined by appearing to be in pain after other causes of pain have been excluded)
4. Able and willing to participate in the study as evidenced by a parent/ legal guardian signing a valid written consent form.
5. All pre existing factors which could contribute to a reduction in BMD such as diet, sunlight exposure, anticonvulsant medication and weight bearing programme have been addressed 6 months prior to commencement of infusion.
6. If female, must have a negative serum pregnancy test at baseline and be using effective contraception if sexually active.
Minimum age
4 Years
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
EXCLUSION CRITERIA
1. Body weight < 10kg.
2. History of cancer within past five years.
3. Untreated rickets within one year of treatment.
4. Documented history of an abnormal or allergic reaction to bisphosphonates.
5. Pubertal delay.
6. Clinically significant abnormal laboratory finding at screening
- Abnormal liver function tests – Alanine Amino Transferase (ALT) & Aspartate Amino Transferase (AST) > 2x upper limit of normal.
- Abnormal thyroid stimulating hormone (TSH) and/ or parathyroid hormone (PTH).
- Serum 25 (OH) vitamin D < 20 nmol/L

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/04/2010
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
10
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 256744 0
Hospital
Name [1] 256744 0
Princess Margaret Hospital for Children
Country [1] 256744 0
Australia
Primary sponsor type
Hospital
Name
Princess Margaret Hospital for Children
Address
Roberts Road
Subiaco
WA6008
Country
Australia
Secondary sponsor category [1] 256026 0
None
Name [1] 256026 0
Address [1] 256026 0
Country [1] 256026 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258758 0
Princess Margaret Hospital for Children Ethics Committee
Ethics committee address [1] 258758 0
Roberts Road
Subiaco
WA6008
Ethics committee country [1] 258758 0
Australia
Date submitted for ethics approval [1] 258758 0
01/07/2009
Approval date [1] 258758 0
20/08/2009
Ethics approval number [1] 258758 0
1698/EP

Summary
Brief summary
Children and teenagers with chronic neurological disease are at risk of having thin bones (osteoporosis). Throughout your life, new bone cells grow and old bone cells break down to make room for the new, stronger bone. Osteoporosis is characterised by the old bone breaking down faster than the new bone can replace it, resulting in the bones losing minerals (such as calcium). This makes bones weaker and more likely to break even after a minor injury. All the bones in your body are weaker if you have osteoporosis but not everyone who has osteoporosis gets a broken bone. Bone pain and fracture are common complications of osteoporosis.
Bisphosphonates are a class of drug that slows down the thinning of bone, and are the standard treatment for osteoporosis in adults. Bisphophonates come in oral and intravenous forms. Gastrointestinal problems and compliance issues associated with oral bisphosphonates can be avoided by the use of intravenous bisphosphonates. Pamidronate, an intravenous bisphosphonate, is given every 6-8 weeks and has been shown to be effective in children. Zoledronate, a new potent intravenous bisphosphonate, is given yearly. Since intravenous bisphosphonates have to be given during a 3 day stay in hospital, zoledronate requires far fewer hospital admissions than does pamidronate.
Trial website
not applicable
Trial related presentations / publications
nil
Public notes

Contacts
Principal investigator
Name 31004 0
Address 31004 0
Country 31004 0
Phone 31004 0
Fax 31004 0
Email 31004 0
Contact person for public queries
Name 14251 0
Gavin Hutana
Address 14251 0
C/- Department Paediatric Rehabilitation
Princess Margaret Hospital for Children
Roberts Road
Subiaco
WA6008
Country 14251 0
Australia
Phone 14251 0
+61 8 9340 8222
Fax 14251 0
+61 8 9340 8001
Email 14251 0
[email protected]
Contact person for scientific queries
Name 5179 0
Gavin Hutana
Address 5179 0
C/- Department Paediatric Rehabilitation
Princess Margaret Hospital for Children
Roberts Road
Subiaco
WA6008
Country 5179 0
Australia
Phone 5179 0
+61 8 9340 8222
Fax 5179 0
Email 5179 0
[email protected]

No information has been provided regarding IPD availability


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.