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Trial registered on ANZCTR


Registration number
ACTRN12618002021257
Ethics application status
Approved
Date submitted
11/12/2018
Date registered
17/12/2018
Date last updated
1/07/2019
Date data sharing statement initially provided
17/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
L-carnitine supplementation for Neurofibromatosis type 1 muscle weakness and fatigue.
Scientific title
A single centre, 12-week, single arm trial to examine compliance, safety and efficacy of daily L-carnitine supplementation (1000mg) for the treatment of childhood Neurofibromatosis Type 1 (NF1)- associated muscle weakness and fatigue.
Secondary ID [1] 296850 0
Nil known
Universal Trial Number (UTN)
U1111-1225-3704
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neurofibromatosis type 1 310756 0
Condition category
Condition code
Musculoskeletal 309447 309447 0 0
Other muscular and skeletal disorders
Metabolic and Endocrine 309448 309448 0 0
Other metabolic disorders
Human Genetics and Inherited Disorders 309484 309484 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
1000 mg daily L-carnitine supplementation for 12 weeks (500 mg oral capsules are to be taken twice daily - once in the morning and once at night).
Intervention code [1] 313130 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 308398 0
Safety will be assessed through adverse-event reporting, Possible adverse events are mild and include a fishy body odour, diarrhea, and vomiting. Individuals are encouraged to report these and will be followed up by a weekly phone call. These will be managed clinically by dose reduction and/or cessation of treatment. A urine sample will be tested at the study end point to confirm normal kidney and liver function.
Timepoint [1] 308398 0
Safety will be assessed throughout the entire experimental period of 12 weeks, and urine will be tested at the 12 week time point.
Primary outcome [2] 308399 0
Compliance will be assessed through counting the number of L-carnitine capsules remaining at the end of the study and subtracting it from the known number of L-carnitine capsules dispensed at the beginning of the trial.
Timepoint [2] 308399 0
Determined at the 12 week time point.
Secondary outcome [1] 354864 0
Multiple measures of strength will be addressed by hand-held dynamometry. The first measure will be grip strength.
Timepoint [1] 354864 0
0, 6 and 12 week timepoints
Secondary outcome [2] 354865 0
Endurance assessed through the 6 minute walk test.
Timepoint [2] 354865 0
0, 6 and 12 week time points
Secondary outcome [3] 354866 0
Power assessed through long jump test.
Timepoint [3] 354866 0
0, 6 and 12 week time points
Secondary outcome [4] 354867 0
Handwriting assessed through handwriting speed test.
Timepoint [4] 354867 0
0, 6 and 12 week time points
Secondary outcome [5] 354869 0
Gait assessed through gait analysis (heel and tip-toe walking).
Timepoint [5] 354869 0
0, 6 and 12 week time points
Secondary outcome [6] 354870 0
Body composition measured through bio electrical impedance.
Timepoint [6] 354870 0
0, 6 and 12 week time points
Secondary outcome [7] 354871 0
Patient reported questionnaires will be given to participants. The first will be the PedsQL (Neuromuscular and Generic Core modules).
Timepoint [7] 354871 0
0, 12 week, and optional 3 month follow up
Secondary outcome [8] 354872 0
Blood tests will be performed for multiple biochemical outcomes. The first will be serum carnitine.
Timepoint [8] 354872 0
0 and 12 week time points
Secondary outcome [9] 354979 0
Multiple measures of strength will be addressed by hand-held dynamometry. The second measure will be lower leg plantarflexion.

Timepoint [9] 354979 0
0, 6 and 12 week time points
Secondary outcome [10] 354980 0
Multiple measures of strength will be addressed by hand-held dynamometry. The third measure will be lower leg dorsiflexion.
Timepoint [10] 354980 0
0, 6 and 12 week time points
Secondary outcome [11] 354981 0
Blood tests will be performed for multiple biochemical outcomes. The second will be serum lipids.
Timepoint [11] 354981 0
0 and 12 week time points
Secondary outcome [12] 354982 0
Patient reported questionnaires will be given to participants. The second will be the Child Behaviour Checklist.
Timepoint [12] 354982 0
0, 12 week, and optional 3 month follow up

Eligibility
Key inclusion criteria
• Children aged between 8-12 years old
• Children with a confirmed clinical diagnosis of NF1 through fulfilling at least two of the NIH diagnostic criteria for NF1 and/or genetic testing
• Children with a medical history of muscle weakness and/or fatigue
• Children that are naïve to nutraceutical supplements, including L-carnitine, and dietary modifications.
Minimum age
8 Years
Maximum age
12 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Children with cognitive impairment, an intellectual disability, or a mental illness
• Children with insufficient knowledge of the English language to complete the required questionnaires during the study
• Children who suffer from seizures
• Children with NF1 skeletal abnormalities (e.g. tibial bowing or pseudarthrosis), acute foot or lower limb injuries (e.g. fracture or ankle sprain)
• Children who are unable to comply with the research protocol (e.g. prolonged absence)

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)
Allocation is not concealed
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
This represents a proof of concept study and data from outcome measures (physiological functional testing and patient questionnaire responses) will be used to guide power calculation for subsequent larger intervention studies. The sample size of n=6 was chosen as it is the size of the cohort in which the maximum tolerated dose would be tested in a phase 1 clinical trial, and thus appropriate to provide estimates for a phase 2 study. While there are no indications that adverse events will be seen in this patient population (and anecdotal evidence indicates that NF1 children thrive on L-carnitine), the first 3 patient will commence treatment 1 month apart. Should no significant adverse events requiring stoppage of the study or clinical intervention occur, subsequent staggering of the next 3 patients will be reduced.
The intervention will be declared safe and feasible if
• No more than 1 of the 6 participants withdraws due to experiencing an adverse event attributable to treatment
• At least 4 of the 6 participants are able to complete at least 75% of the prescribed dose of treatment and comply with study requirements.
NB: In the event of participant withdrawal, we will not be replacing the individual. The number of participant withdrawals will be an indicator of how safe and feasible carnitine supplementation is in this group of NF1 children.
In this study, measures will be taken at the commencement and endpoint of the study (12 weeks) and compared. A subset of measures will be taken at the midpoint of the study (6 weeks). All clinical, demographic and outcome data will be described using standard statistical methods. Due to the likely starting differences between patients (due to age, gender etc), the effects of treatment will be calculated as an average % change (% improvement) for each of the outcome measures (n=6) and confidence intervals for improvement will also be calculated. Patient outcome measures will be statistically compared before and after treatment to reference data obtained by Prof Burns as part of the 1000 Norms project (or other sources) using one-sample t-tests.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 12701 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 25121 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 301422 0
Hospital
Name [1] 301422 0
The Children’s Hospital at Westmead
Address [1] 301422 0
The Children's Hospital at Westmead
178 Hawkesbury Rd , Westmead NSW, 2145
Country [1] 301422 0
Australia
Primary sponsor type
Hospital
Name
The Children's Hospital at Westmead
Address
The Children's Hospital at Westmead
178 Hawkesbury Rd , Westmead NSW, 2145
Country
Australia
Secondary sponsor category [1] 301104 0
None
Name [1] 301104 0
Address [1] 301104 0
Country [1] 301104 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302155 0
Sydney Children's Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 302155 0
Corner Hawkesbury Road and Hainsworth Street
Locked Bag 4001
Westmead NSW 2145
Ethics committee country [1] 302155 0
Australia
Date submitted for ethics approval [1] 302155 0
30/06/2018
Approval date [1] 302155 0
11/09/2018
Ethics approval number [1] 302155 0
HREC/18/SCHN/288

Summary
Brief summary
Neurofibromatosis Type 1 (NF1) is a genetic disorder that affects around 1:3000 individuals worldwide. Individuals with NF1 present with a number of different clinical features including a high tumour burden, skeletal abnormalities and learning difficulties. However, low muscle tone, muscle weakness and fatigue associated with NF1 are being increasingly appreciated as major burdens of disease. These can lead to significant functional impairment and reduced quality of life in children, particularly when combined with other features of NF1 such as learning and behavioural difficulties. A 2006 study showed that approximately 30% of all children with NF1 had low self-concept for physical abilities, which continued into adolescence. There is strong preclinical evidence and anecdotal patient reports to suggest that daily L-carnitine will lead to significant improvements in muscle function (particularly fatiguability) and quality of life in individuals with NF1.

While tumor burden and risk of malignancy can be devastating for affected individuals, musculoskeletal complications such as muscle weakness, scoliosis, and learning difficulties are the most common quality of life burdens in a pediatric setting. L-carnitine supplementation represents a low impact, low cost intervention that could yield major quality of life improvements in a large number of individuals.

The hypothesis to be tested is ‘low dose daily L-carnitine supplementation (1000mg, two divided doses) consumed for 12 weeks is safe and feasible, and will improve muscle strength and endurance in children with NF1.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89314 0
A/Prof Aaron Schindeler
Address 89314 0
The Children's Hospital at Westmead
178 Hawkesbury Rd , Westmead NSW, 2145
Country 89314 0
Australia
Phone 89314 0
+61 404032645
Fax 89314 0
Email 89314 0
aaron.schindeler@sydney.edu.au
Contact person for public queries
Name 89315 0
A/Prof Aaron Schindeler
Address 89315 0
The Children's Hospital at Westmead
178 Hawkesbury Rd , Westmead NSW, 2145
Country 89315 0
Australia
Phone 89315 0
+61 404032645
Fax 89315 0
Email 89315 0
aaron.schindeler@sydney.edu.au
Contact person for scientific queries
Name 89316 0
A/Prof Aaron Schindeler
Address 89316 0
The Children's Hospital at Westmead
178 Hawkesbury Rd , Westmead NSW, 2145
Country 89316 0
Australia
Phone 89316 0
+61 404032645
Fax 89316 0
Email 89316 0
aaron.schindeler@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Results will be disseminated through publications/PhD thesis chapter and conference presentations. We also anticipate that the results of this study will influence the design of a future clinical trial involving nutraceutical supplements or dietary modifications in children with NF1-associated muscle weakness and fatigue. To ensure confidentiality data dispersed will be blinded of any identifying participant information.
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 692 0
Study protocol
Citation [1] 692 0
Link [1] 692 0
Email [1] 692 0
Other [1] 692 0
Type [2] 693 0
Informed consent form
Citation [2] 693 0
Link [2] 693 0
Email [2] 693 0
Other [2] 693 0
Type [3] 694 0
Ethical approval
Citation [3] 694 0
Link [3] 694 0
Email [3] 694 0
Other [3] 694 0
Summary results
No Results