Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12609000315213
Ethics application status
Approved
Date submitted
23/01/2009
Date registered
21/05/2009
Date last updated
12/11/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
Whole Body Vibration Training for Mitochondrial Respiratory Chain Disorders and Rett Syndrome
Scientific title
Does vibration therapy improve physical function and strength in children and adolescents with mitochondrial disorders or Rett syndrome?
Secondary ID [1] 283568 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Mitochondrial respiratory chain disorders 4229 0
Rett syndrome 4230 0
Condition category
Condition code
Human Genetics and Inherited Disorders 4449 4449 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Whole body vibration training (WBVT) using a vibration platform.

WBVT using a vibration platform is a new, simple and safe training method that has been shown to improve muscle mass and bone density. WBVT has been used in a number of clinical settings including healthy athletes, untrained individuals and the elderly and in individuals with cerebral palsy and cystic fibrosis and after stroke. It requires the participant to stand on a vibration plate that moves rapidly (10-20Hz) up and down over a small distance (10mm) generating a vibration stimulus. The vibration causes the muscles in the legs and body to contract resulting in increased muscle mass. WBVT is believed to stimulate bone formation due to the increased forces applied to the bone by the increased muscle mass seen after WBVT. The bone responds to these increased forces by altering its biomechanical properties (mineral content and geometry) to increase its density and strength.
Participants will perform WBVT daily for six months on a vibration plate that will be placed in the participant’s home. Each daily session consists of three 3 minute WBVT sessions with short breaks in between each session. The total daily training time will take about 15 minutes.
Intervention code [1] 3948 0
Treatment: Devices
Comparator / control treatment
Patients will be their own controls - ie looking at before and after measures
Control group
Active

Outcomes
Primary outcome [1] 5330 0
For mitochondrial patients - Peak Jump Force (PJF).

PJF will be assessed by the Single Two-Legged Jump on the Leonardo Jumping Platform (Stratec, Pforzheim, Germany). The child will be instructed to jump as high as possible. A total of 3 jumps will be performed and the jump that results in the maximum PJF will be used for analysis. The raw score and values adjusted for weight and height will be evaluated. Measures of Peak Jump Power (PJP) and Jump Velocity will also be recorded from this test.
Timepoint [1] 5330 0
3 months before commencing therapy, at commencement of therapy and at the end of 6 months of therapy
Primary outcome [2] 5331 0
For mitochondrial and Rett syndrome patients - Dual Energy X-Ray Absorptiometry (DXA).

Total Body, Lumbar Spine and Distal Femur DXA. Variables to be analysed include bone mineral content (BMC) relative to age, body height, body weight, projected bone area and lean tissue mass. Analysis of skeletal subregions (upper limbs, trunk, pelvis, lower limbs) will be performed to assess the site-specificity of the changes compared to normative data. Using subregional analysis, the main outcome parameter is lower extremity bone mineral content. Lower extremity lean tissue mass will also be assessed as will distal femur BMC and areal bone mineral density (aBMD). Other measures include estimated volumetric bone mineral density (vBMD) of the lumbar spine (L2 to L4) and total body BMC and BMD.

DXA directly measures bone mineral content (BMC; expressed in grams) and the bone's two-dimensional projection area (in cm2). aBMD is calculated by dividing the BMC by the projection area (g/cm2). vBMD is the ratio between BMC and extrapolated bone volume (in cm3). Bone volume is derived from bone projection area (in cm2) as described by using the formula: Bone volume = (projection area).
Timepoint [2] 5331 0
3 months before commencing therapy, at commencement of therapy and at the end of 6 months of therapy
Primary outcome [3] 5332 0
For Rett patients - Lower limb skin blood flow measurement.

This will be measured using a moor-LDI2 Laser Doppler Imager (LDI). This operates on the principle that laser light reflected by the skin undergoes a frequency shift that correlates with the movement of red cells, allowing cutaneous perfusion to be determined on a "flux" scale. A 2.25mW near infrared Helium-Neon laser beam is reflected onto the skin surface and the area scanned by sequential movement of a direct current motor controlled mirror in a raster pattern. Light returned from the skin surface is then directed via the same mirror to four photodiodes and the data sent to a Doppler signal processor. An image is then displayed indicating skin blood flow in relative Perfusion Units (PU). An area of 50 x 70 cm may be imaged at a spatial resolution of 1 mm2 within 6 minutes. LDI has been used to determine skin blood flow in patients with contact dermatitis and to predict burn wound outcome in both adults and children. A pilot study using this technology at our institution has confirmed that LDI can measure skin blood flow in the feet of both control and RTT patients (Figure 1). Patients will have both feet imaged after having been positioned on a level surface. The lower limb will then be covered with a warm blanket for 5 minutes before re-imaging skin blood flow in both feet. This will be repeated on two separate occasions at least one day apart. Sequential imaging will be performed immediately before, after and then 10 minutes after the first treatment. Follow-up imaging will then be performed at one week, one month and six months after commencement of treatment.
Timepoint [3] 5332 0
3 months before commencing therapy, at commencement of therapy and at the end of 6 months of therapy
Secondary outcome [1] 8961 0
For mitochondrial patients - Chair Rising Test (CRT).

The CRT will be performed on the Leonardo Jumping Platform (Stratec, Pforzheim, Germany). The child will be seated on the chair with arms crossed in front of them with hands on the shoulders. They will then be asked to stand to an upright position as fast as possible then sit down straight away. This is repeated 5 times in one cycle. Time to perform the test and muscle Power and Force generated during the test will be evaluated.
Timepoint [1] 8961 0
3 months before commencing therapy, at commencement of therapy and at the end of 6 months of therapy
Secondary outcome [2] 8962 0
For mitochondrial patients - Standardized 6 minute walking test.

The standardized 6 minute walking test is a well established objective test of functional exercise capacity, with normative data available for children, which is potentially useful for longitudinal assessment of new treatments in children with neuromuscular disorders. The test will be performed according to the American Thoracic Society guidelines.
Timepoint [2] 8962 0
3 months before commencing therapy, at commencement of therapy and at the end of 6 months of therapy
Secondary outcome [3] 241609 0
For mitochondrial patients - The Newcastle Paediatric Mitochondrial Disease Scale (NPMDS).

The NPMDS allows the evaluation of the progression of mitochondrial disease in patients less than 18 years of age. The rating scale encompasses all aspects of mitochondrial disease by exploring several domains: Current Function; System Specific Involvement; Current Clinical Assessment and Quality of Life. Almost every question in the scale has a possible score from 0-3: 0 representing normal, 1- mild, 2- moderate and 3- severe. In each case, examples of mild, moderate and severe impairment or disability are given. There are three age-specific versions of the NPMDS, 0-24 months, 2-11 years and 12-18 years.
Timepoint [3] 241609 0
3 months before commencing therapy, at commencement of therapy and at the end of 6 months of therapy
Secondary outcome [4] 241610 0
For mitochondrial patients and Rett syndrome - Dietary assessment.

A dietary assessment will be carried out at the times of the DXA, and calcium intake assessed using a usual intake questionnaire of major calcium sources, as well as details about intake of fluids, meat, fruits and vegetables. According to the National Nutrition Survey intake of milk, dairy products and supplements will measure 60-70% of calcium intake. The remaining calcium intake comes from a range of other foods so is not likely to vary much. Calcium intake will be grouped into quartiles or quintiles of calcium intake from major sources based on 250 mg lots (ie <250mg, 250 -500 mg, 500 -750mg etc). Families will be asked not to change the diet, specifically the calcium intake during the study.
Timepoint [4] 241610 0
3 months before commencing therapy, at commencement of therapy and at the end of 6 months of therapy
Secondary outcome [5] 241611 0
For mitochondrial patients and Rett syndrome - Anthropometric measurements.

Accurate measurements of height weight, skin fold thickness, and upper arm circumference, will be taken before and after 6 months of WBVT. Height, weight, Body Mass Index (BMI) and BMI z scores will be calculated from the height and weight measurements.
Timepoint [5] 241611 0
3 months before commencing therapy, at commencement of therapy and at the end of 6 months of therapy
Secondary outcome [6] 241612 0
For mitochondrial patients and Rett syndrome - Biochemical Analyses.

Blood will be collected on the day when WBVT is commenced and at the end of a six month trial period or when WBVT is discontinued by the carer/parent for calcium, phosphorus, alkaline phosphatase, vitamin D levels, osteocalcin and urine deoxypyridinoline.
Timepoint [6] 241612 0
3 months before commencing therapy, at commencement of therapy and at the end of 6 months of therapy
Secondary outcome [7] 241613 0
For Rett syndrome - Patient Questionnaire

The parent/carer of the child will be asked to complete a questionnaire on the acceptability of WBVT at the end of the study.

A Dietary assessment will be carried out at the times of the DXA, and calcium intake assessed using a usual intake questionnaire of major calcium sources, as well as details about intake of fluids, meat, fruits and vegetables. According to the National Nutrition Survey intake of milk, dairy products and supplements will measure 60-70% of calcium intake. The remaining calcium intake comes from a range of other foods so is not likely to vary much. Calcium intake will be grouped into quartiles or quintiles of calcium intake from major sources based on 250 mg lots (ie <250mg, 250 -500 mg, 500 -750mg etc). Families will be asked not to change the diet, specifically the calcium intake during the study.
Timepoint [7] 241613 0
At the end of 6 months of therapy

Eligibility
Key inclusion criteria
For the mitochondrial patients - Children and adolescents aged between 8 – 18 years with a proven mitochondrial respiratory chain disorder, based on positive enzymology in muscle biopsies

for the Rett syndrome patients - Children with Rett syndrome, with known pathogenic Methyl CgP binding protein 2 (MECP2) mutations, up to the age of 18 years
Minimum age
8 Years
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
for mitochondrial patients - anything more than mild cognitive impairment which would impede the ability of test subjects to comply with testing; severe myopathy preventing subjects from being able to stand on the vibration platform for at least 10 minutes; 25-hydroxyvitamin D level < 50 nmol/L; lower limb fracture within the preceding 6 months; use of a medication known to increase bone mass, eg bisphosphonates


for Rett syndrome patients - inability to stand unaided or with the support of a frame on the vibration platform for at least 10 minutes; 25-hydroxyvitamin D level < 50 nmol/L; limb fracture within the preceding 6 months; use of a medication known to increase bone mass, eg bisphosphonates

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
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/03/2009
Actual
2/06/2009
Date of last participant enrolment
Anticipated
Actual
7/02/2012
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 4411 0
Other
Name [1] 4411 0
donated funds, donor wishes to remain anonymous.
Country [1] 4411 0
Australia
Primary sponsor type
Hospital
Name
Children's Hospital at Westmead
Address
Hawkesbury Rd, Westmead, NSw, 2145
Country
Australia
Secondary sponsor category [1] 3969 0
None
Name [1] 3969 0
Address [1] 3969 0
Country [1] 3969 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6458 0
Children's Hospital Westmead Human Research Ethics Committee
Ethics committee address [1] 6458 0
Hawkesbury Rd, Westmead, NSW, 2145
Ethics committee country [1] 6458 0
Australia
Date submitted for ethics approval [1] 6458 0
Approval date [1] 6458 0
03/10/2008
Ethics approval number [1] 6458 0
08/CHW/89

Summary
Brief summary
In the majority of individuals with mitochondrial respiratory chain disorders there is a steady decline with time of muscle mass and strength, and with reducing mobility there is a high risk of reduced bone mineral density and fracture. There are currently no therapies that have been shown to be consistently effective in this cohort of patients.

Rett syndrome is a severe neurodevelopmental disorder. Amongst other clinical problems there is a high risk of reduced bone mass, primarily related to reduced mobility and nutritional intake, and poor perfusion of lower limb extremities.
Aims:
1. To investigate if whole body vibration training is effective and well tolerated over the medium-term in patients with mitochondrial respiratory chain disorders or Rett syndrome.

2. A medium-term home based training program in patients with mitochondrial respiratory chain disorders will evaluate if whole body vibration training influences:
a. Muscle power and force
b. Muscle mass
c. Bone mass

3. A medium-term home based training program in patients with Rett syndrome will evaluate if whole body vibration training influences:
a. Muscle mass
b. Bone mass
c. Lower limb skin blood flow
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29214 0
Prof John Christodoulou
Address 29214 0
Western Sydney Genetics Program Children's Hospital at Westmead Hawkesbury Rd Westmead NSW 2145
Country 29214 0
Australia
Phone 29214 0
+61 2 98453452
Fax 29214 0
Email 29214 0
[email protected]
Contact person for public queries
Name 12461 0
Prof Professor John Christodoulou
Address 12461 0
Western Sydney Genetics Program
Children's Hospital at Westmead
Hawkesbury Rd
Westmead NSW 2145
Country 12461 0
Australia
Phone 12461 0
+61 2 98453452
Fax 12461 0
+61 2 98451864
Email 12461 0
[email protected]
Contact person for scientific queries
Name 3389 0
Prof Professor John Christodoulou
Address 3389 0
Western Sydney Genetics Program
Children's Hospital at Westmead
Hawkesbury Rd
Westmead NSW 2145
Country 3389 0
Australia
Phone 3389 0
+61 2 98453452
Fax 3389 0
+61 2 98451864
Email 3389 0
[email protected]

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No Supporting Document Provided



Results publications and other study-related documents

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