L-Serine Supplementation in Hereditary Sensory Neuropathy Type 1

NCT01733407 | Completed Phase 1 Results DMC

• 1 other identifier: FD-R-04127-01
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 2

Brief Summary

In hereditary sensory and autonomic neuropathy type 1 (HSAN1) the investigators recently discovered the accumulation of two neurotoxic sphingolipids. It appears that these lipids arise as the mutant enzyme has a reduced affinity for its normal preferred substrate L-serine. The investigators now plan to perform a two year study of L-serine supplementation to correct the biochemistry and neurological disease in humans with HSAN1. In the course the investigators will also establish correlations between an existing neurological rating scale of sensory neuropathy and intraepidermal nerve fiber density. Funding Source - FDA OOPD

Conditions

Hereditary Sensory and Autonomic Neuropathy Type I

Keywords

inherited neuropathies

Outcome Measures

Primary Outcomes (1)

• Charcot Marie Tooth Neuropathy Score

  The Charcot Marie Tooth Neuropathy Score (CMTNS) is a 0 to 36 point composite scoring assessment that is used to measure disease severity in Charcot Marie Tooth Neuropathy and other sensory and motor neuropathies. The CMTNS is composed of 9 items that evaluate functions related to disease progression. These 9 parameters include reviewing sensory symptoms, motor symptoms (arms and legs), pinprick sensibility, vibration, leg strength, arm strength, and nerve conduction tests. Each item is scored from 0 to 4, with the lower scores representing less severe symptoms and higher scores representing more severe symptoms.The 9 individual item scores are then totaled to provide a global measure of disease severity. For example the lowest possible total score is 0 which represents an asymptomatic individual and the highest score possible is a 36 which represents an individual with severe disease progression. There are sub scores that can be assessed but sub scores were not utilized in this study

  48 Weeks

Secondary Outcomes (5)

• Intraepidermal Nerve Fiber Density (IENFD)

  48 Weeks

• Autonomic Function Testing (AFT) Composite Autonomic Severity Score (CASS)

  48 Weeks

• Nerve Conduction Testing

  48 Weeks

• 1-deoxy-sphinganine

  48 Weeks

• 1-deoxy-sphingosine

  48 weeks

Study Arms (2)

Sugar pill

PLACEBO COMPARATOR

Placebo arm

Drug: placebo

L-serine

ACTIVE COMPARATOR

amino acid supplementation with L-serine

Drug: L-serine

Interventions

L-serine DRUG

400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2.

Also known as: amino acid supplementation with L-serine

L-serine

placebo DRUG

400mg/kg/d divided TID for year 1 only.

Also known as: sugar pill

Sugar pill

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HSAN1 patients with prominent sensory loss with foot ulcers or shooting pains and con-firmed mutations in SPTLC1.
• Males and females of 18 years or older
• All patients will be able to provide informed consent and comply with oral dietary supple-mentation and study activities. Compliance with supplementation will be monitored through measurement of DSB levels.
• Subjects must not have taken L-serine for at least 30 days prior to randomization (L-serine-naïve subjects are permitted in the study).
• Women must not become pregnant for the duration of the study and must be willing to use two contraceptive therapies and have a negative pregnancy test throughout the course of the study.

You may not qualify if:

• Any cause of neuropathy other than HSAN1 (such as diabetes or drug-induced neuropathy), medical history of kidney stones, or history of poliomyelitis or radiotherapy.
• Pregnant women, breastfeeding, or not using adequate contraception; for women included, an accepted method of contraception will be used throughout the study.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Patients on blood-thinners such as warfarin (Coumadin) or heparin will not be biopsied until they have held the medication for 5 days. Following the biopsy they will resume the maintenance dose of their medication.
• Serious illness (requiring systemic treatment and/or hospitalization) until subject either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 10 days prior to study entry.
• The presence of unstable psychiatric disease, cognitive impairment, or dementia that would impair ability of the subject to provide informed consent, according to PI judgment, or a history of active substance abuse within the prior year.
• Subjects who are non-ambulatory.
• Subjects with uncontrolled diabetes.
• Patients who are unable or unwilling to give consent will not be enrolled in the study.

Sponsors & Collaborators

• Massachusetts General Hospital: lead

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

UMass Medical Center

Worcester, Massachusetts, 01605, United States

Location

Related Publications (2)

• Garofalo K, Penno A, Schmidt BP, Lee HJ, Frosch MP, von Eckardstein A, Brown RH, Hornemann T, Eichler FS. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest. 2011 Dec;121(12):4735-45. doi: 10.1172/JCI57549.

  PMID: 22045570 BACKGROUND

• Fridman V, Suriyanarayanan S, Novak P, David W, Macklin EA, McKenna-Yasek D, Walsh K, Aziz-Bose R, Oaklander AL, Brown R, Hornemann T, Eichler F. Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1. Neurology. 2019 Jan 22;92(4):e359-e370. doi: 10.1212/WNL.0000000000006811. Epub 2019 Jan 9.

  PMID: 30626650 DERIVED

MeSH Terms

Conditions

Hereditary Sensory and Autonomic Neuropathies

Interventions

Serine; Sugars

Condition Hierarchy (Ancestors)

Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins; Carbohydrates

Results Point of Contact

• Title: Dr. Florian Eichler
• Organization: Massachusetts General Hospital

Feichler@partners.org

617-643-3799

Study Officials

• Florian S Eichler, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Neurology

Study Record Dates

• First Submitted: September 19, 2012
• First Posted: November 27, 2012
• Study Start: September 1, 2013
• Primary Completion: May 1, 2016
• Study Completion: July 1, 2017
• Last Updated: September 12, 2018
• Results First Posted: September 12, 2018

Record last verified: 2018-08

Locations

US (2)