ANZCTR - Registration

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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

23/05/2022

Date data sharing statement initially provided

17/12/2018

Date results provided

23/05/2022

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]

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

Condition category

Condition code

Musculoskeletal

Other muscular and skeletal disorders

Metabolic and Endocrine

Other metabolic disorders

Human Genetics and Inherited Disorders

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]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

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]

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]

Determined at the 12 week time point.

Secondary outcome [1]

Multiple measures of strength will be addressed by hand-held dynamometry. The first measure will be grip strength.

Timepoint [1]

0, 6 and 12 week timepoints

Secondary outcome [2]

Endurance assessed through the 6 minute walk test.

Timepoint [2]

0, 6 and 12 week time points

Secondary outcome [3]

Power assessed through long jump test.

Timepoint [3]

0, 6 and 12 week time points

Secondary outcome [4]

Handwriting assessed through handwriting speed test.

Timepoint [4]

0, 6 and 12 week time points

Secondary outcome [5]

Gait assessed through gait analysis (heel and tip-toe walking).

Timepoint [5]

0, 6 and 12 week time points

Secondary outcome [6]

Body composition measured through bio electrical impedance.

Timepoint [6]

0, 6 and 12 week time points

Secondary outcome [7]

Patient reported questionnaires will be given to participants. The first will be the PedsQL (Neuromuscular and Generic Core modules).

Timepoint [7]

0, 12 week, and optional 3 month follow up

Secondary outcome [8]

Blood tests will be performed for multiple biochemical outcomes. The first will be serum carnitine.

Timepoint [8]

0 and 12 week time points

Secondary outcome [9]

Multiple measures of strength will be addressed by hand-held dynamometry. The second measure will be lower leg plantarflexion.

Timepoint [9]

0, 6 and 12 week time points

Secondary outcome [10]

Multiple measures of strength will be addressed by hand-held dynamometry. The third measure will be lower leg dorsiflexion.

Timepoint [10]

0, 6 and 12 week time points

Secondary outcome [11]

Blood tests will be performed for multiple biochemical outcomes. The second will be serum lipids.

Timepoint [11]

0 and 12 week time points

Secondary outcome [12]

Patient reported questionnaires will be given to participants. The second will be the Child Behaviour Checklist.

Timepoint [12]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Completed

Date of first participant enrolment

Anticipated

4/02/2019

Actual

13/06/2019

Date of last participant enrolment

Anticipated

1/10/2019

Actual

1/10/2019

Date of last data collection

Anticipated

31/12/2019

Actual

31/12/2019

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

The Children's Hospital at Westmead - Westmead

Recruitment postcode(s) [1]

2145 - Westmead

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

The Children’s Hospital at Westmead

Address [1]

The Children's Hospital at Westmead
178 Hawkesbury Rd , Westmead NSW, 2145

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Sydney Children's Hospitals Network Human Research Ethics Committee

Ethics committee address [1]

Corner Hawkesbury Road and Hainsworth Street
Locked Bag 4001
Westmead NSW 2145

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

30/06/2018

Approval date [1]

11/09/2018

Ethics approval number [1]

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

A/Prof Aaron Schindeler

Address

The Children's Hospital at Westmead
178 Hawkesbury Rd , Westmead NSW, 2145

Country

Australia

Phone

+61 404032645

Fax

aaron.schindeler@sydney.edu.au

Contact person for public queries

Name

Aaron Schindeler

Address

The Children's Hospital at Westmead
178 Hawkesbury Rd , Westmead NSW, 2145

Country

Australia

Phone

+61 404032645

Fax

aaron.schindeler@sydney.edu.au

Contact person for scientific queries

Name

Aaron Schindeler

Address

The Children's Hospital at Westmead
178 Hawkesbury Rd , Westmead NSW, 2145

Country

Australia

Phone

+61 404032645

Fax

aaron.schindeler@sydney.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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?

Doc. No.	Type	Attachment
692	Study protocol	376564-(Uploaded-11-12-2018-15-29-33)-Study-related document.docx
693	Informed consent form	376564-(Uploaded-11-12-2018-15-25-23)-Study-related document.docx
694	Ethical approval	376564-(Uploaded-11-12-2018-15-25-23)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	L-carnitine supplementation for muscle weakness and fatigue in children with neurofibromatosis type 1: A Phase 2a clinical trial.	2021	https://dx.doi.org/10.1002/ajmg.a.62392

N.B. These documents automatically identified may not have been verified by the study sponsor.

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