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Trial registered on ANZCTR


Registration number
ACTRN12619000561189
Ethics application status
Approved
Date submitted
2/04/2019
Date registered
10/04/2019
Date last updated
10/04/2019
Date data sharing statement initially provided
10/04/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Hereditary sensory neuropathy type 1 (HSN1) treatment trial.
Scientific title
Hereditary sensory neuropathy type 1 (HSN1) treatment trial to evaluate the effect of L-serine on peripheral nerve function.
Secondary ID [1] 292236 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hereditary sensory neuropathy type 1A with SPTLC1 mutations 303735 0
Hereditary sensory neuropathy type 1B with SPTLC2 mutations 303736 0
Condition category
Condition code
Neurological 303109 303109 0 0
Neurodegenerative diseases
Human Genetics and Inherited Disorders 310812 310812 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Ingredient: L-serine
Molecular Weight: 105.09 g/mol
Quantity (strength): 100% (100% supplement)

- the dose administered is 400 mg/kg/body weight/day, spread over 3 doses per day. For example: the daily dose for a patient weighing 75 kg is 30 g (10 g consumed three times per day).
- the duration of administration is 24 months.
- the mode of administration is a white crystalline powder mixed with water for oral consumption.

Adherence will be monitored by taking blood samples every 6 months for L-serine amino acid quantitation analysis.

A participant diary sheet will also be provided to participants to log any missed doses.
Intervention code [1] 298396 0
Treatment: Drugs
Comparator / control treatment
Comparison on and off treatment. No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 302484 0
Proximal migration or no change in the sensory levels of sharp sensation (measured using a Neuro Tip modality) and/or dull sensation (measured using a Paperclip modality).
Timepoint [1] 302484 0
Assessed every 6 months for 48 months post-enrollment.
Primary outcome [2] 302485 0
Skin biopsy small nerve fiber density counts at, above and below mean sensory level.
Timepoint [2] 302485 0
Assessed every 6 months for 48 months post-enrollment.
Primary outcome [3] 302486 0
Plasma sphingolipid levels.
Timepoint [3] 302486 0
Assessed every 6 months for 48 months post-enrollment.
Secondary outcome [1] 336153 0
Neurophysiology and nerve conduction studies assessed using the CMT Neuropathy Score - Version 2 (Murphy S, Herrmann D, McDermott M, Scherer S, Shy M, Reilly M, and Pareyson D. Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2011; 16(3): 191–198).
Timepoint [1] 336153 0
Assessed every 6 months for 48 months post-enrollment.
Secondary outcome [2] 336155 0
Quality of life assessed using Table 2 of CMTNS spoken instructions (Murphy S, Herrmann D, McDermott M, Scherer S, Shy M, Reilly M, and Pareyson D. Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2011; 16(3): 191–198).
Timepoint [2] 336155 0
Assessed every 6 months for 48 months post-enrollment.
Secondary outcome [3] 336156 0
Quality of life assessed using the Modified Ranking Scale (mRS) (Wilson JT, Hareendran A, Grant M, Baird T, Schulz UG, Muir KW, and Bone I. Improving the assessment of outcomes in stroke: Use of a Structured Interview to Assign Grades on the Modified Rankin Scale. Stroke 2002 Sep;33(9):2243-6.
Timepoint [3] 336156 0
Assessed every 6 months for 48 months post-enrollment.
Secondary outcome [4] 336157 0
Quality of life assessed using the Australian Quality of Life 8D (AQOL-8D) questionnaire (Richardson J., Iezzi A., Khan M.A., and Maxwell A (2013). Validity and reliability of the Assessment of Quality of Life (AQoL-8D) multi attribute utility instrument. The Patient: Patient-Centered Outcomes Research, (DOI 10.1007/s40271-013-0036-x).
Timepoint [4] 336157 0
Assessed every 6 months for 48 months post-enrollment.
Secondary outcome [5] 336158 0
Quality of life assessed using the Australian CMT Health Survey (Redmond AC, Burns J, and Ouvrier RA. Factors that influence health-related quality of life in Australian adults with Charcot-Marie-Tooth disease. NMD 2008; 18:619-625). .
Timepoint [5] 336158 0
Assessed every 6 months for 48 months post-enrollment.
Secondary outcome [6] 336159 0
Peripheral muscle strength measured using a dynamo meter (Solari A, Laura M, Salsano E, et al. Reliability of clinical outcome measures in Charcot-Marie-Tooth disease. Neuromuscular Disorders. 2008;18:19-26). (Burns J, Ouvrier R, Estilow T, Shy R, Laura M, Pallant J, Lek M, Muntoni F, Reilly M, Pareyson D, Acsadi G, Shy M, and Finkel R. Validation of the CMT Pediatric Scale as an outcome measure of disability. Annals of Neurology 71(5). 642-652, 2012).
Timepoint [6] 336159 0
Assessed every 6 months for 48 months post-enrollment.
Secondary outcome [7] 336160 0
Functional endurance assessed using the 6 minute walk test (McDonald CM, Henricson EK, Han JJ, et al. The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve. 2010;41;500-510).
Timepoint [7] 336160 0
Assessed every 6 months for 48 months post-enrollment.
Secondary outcome [8] 336161 0
Plasma serine levels.
Timepoint [8] 336161 0
Assessed every 6 months for 48 months post-enrollment.
Secondary outcome [9] 368911 0
CMT Clinic - Minimal Dataset Form (Inherited Neuropathies Consortium. Rare Clinical Diseases Research Network. [URL=https://www.rarediseasesnetwork.org/cms/inc/] (Page updated 25th April 2016).

This form will quantify participant's lifestyle and functionality limitations.
Timepoint [9] 368911 0
Assessed every 6 months for 48 months post-enrollment.

Eligibility
Key inclusion criteria
-Participants tested positive to SPTLC1 mutations.
-Participants showing signs and symptoms of HSN1.
-Participants able to visit the clinic in Sydney, Australia (geographically close proximity).
-Ambulant subjects.
-Participants only taking part in 1 clinical trial at a time.
-Participants that are able to provide acceptable/accurate reproducible sensory level measurements.
Minimum age
16 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Participants whom have the presence of other forms of neuropathy e.g.-diabetes.
-Participants already taking L-serine.
-Participants highly dependent on medical care.
-Participants with severe nerve degeneration.
-Existing alcohol or drug abusers.
-Pregnant women.

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
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Our current sample size includes 12 participants with aims to recruit additional participants as this may strengthen the validity of this study and provide extra study 'power' to the data and results obtained.

Data is inputted and analysed using Microsoft Excel, SPSS and R - The R project for Statistical Computing,

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)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 296783 0
Charities/Societies/Foundations
Name [1] 296783 0
Charcot-Marie-Tooth Association of Australia (CMTAA)
Address [1] 296783 0
Building 22, Concord Hospital,
Concord,
NSW, 2139.
Country [1] 296783 0
Australia
Funding source category [2] 302381 0
Hospital
Name [2] 302381 0
Concord Repatriation General Hospital
Address [2] 302381 0
Hospital Road,
Concord,
NSW, 2139.
Country [2] 302381 0
Australia
Primary sponsor type
Hospital
Name
Concord Repatriation General Hospital
Address
Hospital Road,
Concord,
NSW, 2139.
Country
Australia
Secondary sponsor category [1] 302267 0
None
Name [1] 302267 0
Address [1] 302267 0
Country [1] 302267 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298007 0
Sydney Local Health District Human Research Ethics Committee - CRGH
Ethics committee address [1] 298007 0
Concord Repatriation General Hospital (CRGH)
Hospital Road, Concord,
NSW, 2139.
Ethics committee country [1] 298007 0
Australia
Date submitted for ethics approval [1] 298007 0
Approval date [1] 298007 0
10/07/2018
Ethics approval number [1] 298007 0
HREC/18/CRGH/15; CH62/6/2018-009

Summary
Brief summary
This study aims to determine whether dietary supplementation with L-serine improves clinical effects of hereditary sensory neuropathy type 1 (HSN1). The most prevalent form of HSN1 is caused by variations (mutations) in the serine palmitoyltransferase (SPT) gene. Deoxysphingolipid bases are toxic by-products produced by mutations in the SPT gene. In a rat model of HSN1, dietary supplementation with the amino acid, L-serine, reduced levels of deoxysphingolipid bases (Garofalo K, Penno A, Schmidt BP, et al. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest 2011;121:4735-4745).

Serine treatment may prevent the clinical accompaniments of this disease which include sensory loss, insensitivity to pain and varying degrees of muscle weakness and wasting. Frequent complications in HSN1 are foot ulceration's, infections and limb amputations.

We wish to determine the power of various modalities of testing (skin sensitivity testing, skin biopsy and standard clinical and neurophysiology measures) for a larger trial.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75714 0
Prof Garth A. Nicholson
Address 75714 0
Clinical Sciences Building
Concord Repatriation General Hospital
Concord NSW 2139
Country 75714 0
Australia
Phone 75714 0
+61 2 9767 6796
Fax 75714 0
+61 2 9767 6194
Email 75714 0
garth.nicholson@sydney.edu.au
Contact person for public queries
Name 75715 0
Prof Garth A. Nicholson
Address 75715 0
Clinical Sciences Building
Concord Repatriation General Hospital
Concord NSW 2139
Country 75715 0
Australia
Phone 75715 0
+61 2 9767 6796
Fax 75715 0
+61 2 9767 6194
Email 75715 0
garth.nicholson@sydney.edu.au
Contact person for scientific queries
Name 75716 0
Prof Garth A. Nicholson
Address 75716 0
Clinical Sciences Building
Concord Repatriation General Hospital
Concord NSW 2139
Country 75716 0
Australia
Phone 75716 0
+61 2 9767 6796
Fax 75716 0
+61 2 9767 6194
Email 75716 0
garth.nicholson@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
If participant data is made available during the trial, it may cause bias and affect trial results.
What supporting documents are/will be available?
No other documents available
Summary results
No Results