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Trial registered on ANZCTR


Registration number
ACTRN12619001372178
Ethics application status
Approved
Date submitted
3/09/2019
Date registered
8/10/2019
Date last updated
8/10/2019
Date data sharing statement initially provided
8/10/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
The effects of pubertal induction on bone health in children with neuromuscular conditions
Scientific title
The effects of pubertal induction on bone health in children with neuromuscular conditions
Secondary ID [1] 299343 0
none
Universal Trial Number (UTN)
Trial acronym
PIMS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cerebral palsy 314238 0
Spinal muscular atrophy 314239 0
Muscular dystrophies 314242 0
Condition category
Condition code
Neurological 312603 312603 0 0
Other neurological disorders
Musculoskeletal 312834 312834 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
BOYS: transdermal testosterone (Testogel) rubbed into the thigh daily (either dispensed via sachet or pump depending on product availability)
GIRLS: transdermal oestrogen patch (Climara) placed on hairless skin area weekly (continuously for 7 days)


Please see algorithm for dose changes below: All dosing changes are based on the participant’s preceding visit.

BOYS:

Screening – 3 months:
All participants will start at ½ Sachet or 2 actuations of pump daily

At 3 months visit:
If there is an increase of AT LEAST one level of Tanner staging = No changes
If there is no changes to puberty = Increase to 1 sachet /day (for sachets) or 4 actuations daily (for pump)

At 6 months visit:
If there is an increase of AT LEAST one level of Tanner staging = No changes
If there is no changes to puberty and patient is only on starting dose= Increase to 1 sachet/4 actuations daily
If there is no changes to puberty and patient is currently on 1 sachet/4 actuations, increase to 2 sachets daily/8 actuations daily

At 9 months visit:
If there is an increase of AT LEAST one level of Tanner staging = No changes
If there is no changes to puberty and patient is only on starting dose= Increase to 1 sachet/4 actuations daily
If there is no changes to puberty and patient is currently on 1 sachet/4 actuations, increase to 2 sachets daily/8 actuations daily
If there is no changes to puberty and patient is currently on 2 sachets daily/8 actuations daily, make no further changes as this is the maximum dose.

At 12 months visit:
If there is an increase of AT LEAST one level of Tanner staging = No changes
If there is no changes to puberty and patient is only on starting dose= Increase to 1 sachet/4 actuations daily
If there is no changes to puberty and patient is currently on 1 sachet/4 actuations, increase to 2 sachets daily/8 actuations daily
If there is no changes to puberty and patient is currently on 2 sachets daily/8 actuations daily, make no further changes as this is the maximum dose.

From 12- 24 months visit:
No further changes to dosage - maintain current dose

GIRLS:
Screening – 3 months:
All participants will start at ½ patch of Climara® 25, weekly

At 3 months visit:
If patient has an increase of AT LEAST one level of Breast Tanner staging = No changes
If patient has no changes to puberty = Increase to one patch of Climara® 25 weekly

At 6 months visit:
If patient has an increase of AT LEAST one level of Breast Tanner staging = No changes
If patient has no changes to puberty and is on the starting dose= Increase to one patch of Climara® 25 weekly
If patient has no changes to puberty and is currently on 1 full patch of Climara® 25 weekly = increase to 1 and a half patches of Climara® 25 weekly

At 9 months visit:
If patient has an increase of AT LEAST one level of Breast Tanner staging = No changes
If patient has no changes to puberty and is on the starting dose= Increase to one patch of Climara® 25 weekly
If patient has no changes to puberty and is currently on 1 full patch of Climara® 25 weekly = increase to 1 and a half patches of Climara® 25 weekly
If patient has no changes to puberty and is currently on 1 and half patches of Climara® 25 weekly = increase to one patch of Climara® 50 weekly

At 12 months visit:
If patient has an increase of AT LEAST one level of Breast Tanner staging = No changes
If patient has no changes to puberty and is on the starting dose= Increase to one patch of Climara® 25 weekly
If patient has no changes to puberty and is currently on 1 full patch of Climara® 25 weekly = increase to 1 and a half patches of Climara® 25 weekly
If patient has no changes to puberty and is currently on 1 and half patches of Climara® 25 weekly = increase to one patch of Climara® 50 weekly
If patient has no changes to puberty and is currently on 1 full patch of Climara® 50 weekly = no changes as this is the maximum dose
From 12- 24 months visit:
No further changes to dosage - maintain current dose

Medication refills will occur 3-monthly. Compliance will be monitored by counting scripts not filled (from missed visits) and unused patches, as well as self-reports by patient using medication log/diary. For those who decline treatment, these children will undergo the assessments at baseline, 12 and 24 months as outlined previously without the 3 monthly check-ups.
Intervention code [1] 315451 0
Treatment: Drugs
Comparator / control treatment
The control group will be formed of only the participants who have declined treatment.
Control group
Active

Outcomes
Primary outcome [1] 321249 0
Primary outcome measure will be bone mass as assessed by Bone mineral density (BMD) using Dual energy X-ray Absorptiometry (DXA) scan for trabecular bone and Peripheral Quantitative Computerised Tomography (pQCT)
Timepoint [1] 321249 0
Baseline, 12 and 24 months.
Secondary outcome [1] 374449 0
fracture incidence as detected by review of Xrays
Timepoint [1] 374449 0
baseline, 12 and 24 months
Secondary outcome [2] 374967 0
Quality of life (QoL) scores from WHOQOL-BREF
Timepoint [2] 374967 0
baseline, 12 and 24 months
Secondary outcome [3] 374968 0
change in physical activity using International Physical Activity Questionnaire (IPAQ)
Timepoint [3] 374968 0
baseline, 12 and 24 months
Secondary outcome [4] 374969 0
change in mobility via 6 minute walk test
Timepoint [4] 374969 0
baseline, 12 and 24 months
Secondary outcome [5] 374970 0
change in Parathyroid levels in blood
Timepoint [5] 374970 0
baseline, 12 and 24 months
Secondary outcome [6] 374971 0
change in strength via grip strength test using hand dynamometer
Timepoint [6] 374971 0
baseline, 12 and 24 months
Secondary outcome [7] 375394 0
change in alkalaine phosphatase levels in blood
Timepoint [7] 375394 0
baseline, 12 and 24 months
Secondary outcome [8] 375395 0
change in vitamin d levels in blood
Timepoint [8] 375395 0
baseline, 12 and 24 months

Eligibility
Key inclusion criteria
Participants will include girls 13 years and over, and boys 14.5 years and older, who have not reached puberty as defined by onset of breast development in girls, testicular enlargement in boys >4ml , with associated and continuing changes in feminization or virilisation over at least 6 months and who have one of the following conditions

1) Spinal muscular atrophy Types 2 & 3
2) Cerebral palsy with a level 4 or 5 on the Gross Motor Function Classification System (GMFCS)
3) Muscular dystrophies other than Duchenne (eg Becker) and congenital myopathies
(eg. Nemaline )
Minimum age
13 Years
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Children who
• Have Duchenne Muscular Dystrophy (because of corticosteroid use interferes with pubertal onset and progress)
• Are currently participating in other trials because altered pubertal status is likely to affect other care aspects in many areas
• Are using or have prior use of bisphosphonates or other bone modifying drugs
• Have used corticosteroids for the last 12 months
• Has active or completed puberty
• Have a contraindication to Androgens (Testogel®) or oestrogens (Climara®) use due to a severe pro-coagulopathic disorder or medication allergies
• Have vertebral fractures greater than Genant 3 found on back x-ray at screening or 6 months prior as this will require bisphosphonate treatment
• Previous incidences of deep vein thrombosis, clots or stroke
• Older than 18 years of age

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 3 / Phase 4
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
18/09/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
58
Accrual to date
6
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 14700 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 27736 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 303706 0
Charities/Societies/Foundations
Name [1] 303706 0
Foundation for Children
Country [1] 303706 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Murdoch Childrens Research Institute
Address
Murdoch Childrens Research Institute,
The Royal Children’s Hospital
50 Flemington Road, Parkville, VIC 3052
Country
Australia
Secondary sponsor category [1] 303815 0
None
Name [1] 303815 0
Address [1] 303815 0
Country [1] 303815 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304231 0
Royal Childrens Hospital Human and Research Ethics Committee
Ethics committee address [1] 304231 0
The Royal Children’s Hospital
50 Flemington Road, Parkville, VIC 3052
Ethics committee country [1] 304231 0
Australia
Date submitted for ethics approval [1] 304231 0
Approval date [1] 304231 0
14/09/2017
Ethics approval number [1] 304231 0

Summary
Brief summary
This study is a prospective, interventional study of bone health in children with neuromuscular diseases conducted at The Royal Children’s Hospital, Melbourne.
The effect(s) of pubertal induction in paediatric neuromuscular diseases have not been formally studied. Our main aim is to provide evidence as to whether pubertal induction may improve bone health and quality of life in children and adolescents with significant neuromuscular disabilities and reduce burden of care on families. Children with neuromuscular disabilities are often very thin and have poor muscle strength and stability, which increases fall frequency and risk of fracture and often have delayed or arrested puberty. Puberty is a crucial time for bone mass accrual and therefore, an optimal time for clinicians to intervene to improve bone health.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 96218 0
Prof margaret zacharin
Address 96218 0
Royal Childrens Hospital
50 Flemington Rd Parkville VIC 3052
Country 96218 0
Australia
Phone 96218 0
+61 393454214
Fax 96218 0
Email 96218 0
margaret.zacharin@rch.org.au
Contact person for public queries
Name 96219 0
margaret zacharin
Address 96219 0
Royal Childrens Hospital
50 Flemington Rd Parkville VIC 3052
Country 96219 0
Australia
Phone 96219 0
+61 393454214
Fax 96219 0
Email 96219 0
margaret.zacharin@rch.org.au
Contact person for scientific queries
Name 96220 0
margaret zacharin
Address 96220 0
Royal Childrens Hospital
50 Flemington Rd Parkville VIC 3052
Country 96220 0
Australia
Phone 96220 0
+61 393454214
Fax 96220 0
Email 96220 0
margaret.zacharin@rch.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


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.