Hereditary Sensory Neuropathy Serine Trial (SENSE)

Randomised, Double Blind, Placebo-controlled Trial of L-serine in Hereditary Sensory Neuropathy Type 1.

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.

Study Overview

• Status: Recruiting
• Conditions: Hereditary Sensory Neuropathy Type I
• Intervention / Treatment: Drug: Placebo; Drug: L-serine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Recruiting
    • University College London
    • Contact: Lodina Recica; Phone Number: 02034488011; Email: lodina.recica.21@ucl.ac.uk
    • Sub-Investigator: Caroline Kramarz
    • Principal Investigator: Mary M Reilly

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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).	Drug: L-serine; Active comparator
Placebo Comparator: 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).	Drug: Placebo; Placebo comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRC Muscle Fat Fraction protocol	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.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary outcome measures	Charcot Marie Tooth Neuropathy Score (CMTNS) v2 and v2-Rasch	12 months
Secondary/Exploratory outcome measures	plasma neurofilament light chain levels	12 months
Secondary/Exploratory outcome measures	plasma deoxysphingolipid levels	12 months
Secondary/Exploratory outcome measures	thigh intraepidermal nerve fibre density	12 months
Secondary outcome measures	Charcot Marie Tooth Health Index Quality of Life Score	12 months
Secondary outcome measure	Neuropathic Pain Diagnostic Questionnaire	12 months
Secondary outcome measure	Neuropathic Pain Symptom Inventory	12 months
Secondary outcome measure	Brief Pain Inventory	12 months

Collaborators and Investigators

• Sponsor: University College, London

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2023
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: October 12, 2023
• First Submitted That Met QC Criteria: October 31, 2023
• First Posted (Actual): November 2, 2023

Study Record Updates

• Last Update Posted (Actual): November 2, 2023
• Last Update Submitted That Met QC Criteria: October 31, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Polyneuropathies; Hereditary Sensory and Autonomic Neuropathies
• Other Study ID Numbers: 1006207

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No