Randomised, Double Blind, Placebo-controlled Trial of L-serine in Hereditary Sensory Neuropathy Type 1.
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- MRC Muscle Fat Fraction protocol
研究概览
简要总结
This is a randomised double-blind placebo-controlled trial of L-serine in Hereditary Sensory Neuropathy type 1 (HSN1) due to variants in SPTLC1/2 gene.
This is a single-centre study being conducted at the National Hospital for Neurology and Neurosurgery, London UK.
The SENSE trial will test whether L-serine is an effective drug treatment to slow or stop disease progression in HSN1 due to variants in the SPLTLC1 or SPTLC2 gene. The other aim is to assess if Magnetic Resonance Imaging (MRI) can accurately detect the changes which occur in the muscles of people who have HSN1.
详细描述
Hereditary Sensory Neuropathy (HSN) represents a subgroup of disorders called Charcot Marie Tooth (CMT) disease. Hereditary Sensory Neuropathy Type 1 (HSN1) is the most common subtype. It is a rare autosomal dominant (AD) neuropathy characterised by severe sensory and motor involvement for which there is no current treatment. HSN1 secondary to SPTLC1/2 mutations is the commonest type of HSN. The neuropathy is slowly progressive with onset between the second and fifth decade. The profound sensory involvement is associated with painless ulcers, recurrent osteomyelitis, and amputations. The neuropathy is very painful and pain medications are rarely fully efficacious. Motor involvement invariably follows leading to significant disability. HSN1 is due to mutations in the SPTLC1 and more rarely SPTLC2 genes which encode for the first two (out of 3) subunits of the enzyme serine palmitoyl transferase (SPT) which catalyses the first and rate limiting step in de novo sphingolipid biosynthesis. Mutations in SPTLC1 and SPTLC2 cause the neuropathy by a gain of function mechanism as mutations alter the substrate specificity of SPT whereby alanine and glycine are preferred over the canonical serine resulting in the production of neurotoxic deoxysphingolipids (DSBs).
This single-site double-blinded placebo-controlled trial will investigate whether L-serine is efficacious in the treatment of HSN1 due to SPTLC1/2 mutations.
The primary objective is to identify if treatment with L-serine is efficacious in the treatment of HSN1 due to SPTLC1/2 mutations compared to treatment with placebo. A major objective will be to validate the use of the MRC Muscle Fat Fraction protocol as a primary outcome measure in inherited neuropathies trials. The MRC Muscle Fat Fraction protocol has been shown to be a responsive biomarker in natural history studies in several inherited neuropathies including HSN, but not previously in clinical trials. Regardless of the efficacy outcome, the trial will assess the feasibility of MRI as an outcome measure in a clinical trial setting, and comparison of the results in the placebo arm to previous natural history study data will validate the translation of natural history results to the clinical trial setting.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants aged ≥ 18 with genetically proven HSN1 due to SPTLC1/2 mutations.
- •Participants must be able to undergo an MRI scan without sedation.
- •Participants must be able to complete the Charcot Marie Tooth Neuropathy Score (CMTNS)
- •Participants must have a CMTES ≤ 26
- •Female participants of childbearing potential must agree to use a highly effective method of contraception from the time consent is signed until six days after treatment discontinuation (this is to allow for medication wash out post treatment discontinuation).
- •Participants must be willing and able to provide written informed consent.
排除标准
- •Participants have undergone foot surgery in the 6 months prior to trial enrolment or are due to undergo foot surgery during the trial
- •Participants have a history of nephrolithiasis
- •Participants have another medical condition which precludes them from having an MRI scan or from completing the CMTNSv2
- •Participants with known diagnosis of another neuromuscular disease
- •Participants with diabetes
- •Females who are planning pregnancy or are pregnant or breastfeeding.
- •Patient taking regular L-serine supplementation within 6 months of study commencement.
研究组 & 干预措施
L-serine
L-serine white or almost white crystalline powder or colourless crystal formulation which will be dissolved in water and administered orally.
The dose will be weight based: 400mg/kg/day (total daily dose).
干预措施: L-serine (Drug)
Dextrose
Dextrose monohydrate powder: monohydrate form of crystalline D-glucose (dextrose) consisting of odourless, multi-granular white crystals.
The dose will be weight based: 400mg/kg/day (total daily dose).
干预措施: Placebo (Drug)
结局指标
主要结局
MRC Muscle Fat Fraction protocol
时间窗: 12 months
The primary outcome measure will be the mean difference in change from baseline lower limb muscle fat fraction at the severity appropriate anatomical level measured by MRI over 12 months between L-serine treated and placebo treated groups. The primary outcome has units of percentage fat fraction (%FF) and is a continuous variable.
次要结局
- Secondary outcome measures(12 months)
- Secondary outcome measure(12 months)
- Secondary/Exploratory outcome measures(12 months)