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L-Serine Supplementation in Hereditary Sensory Neuropathy Type 1

This study is not yet open for participant recruitment.
Verified November 2012 by Massachusetts General Hospital
Sponsor:
Information provided by (Responsible Party):
Florian Eichler, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT01733407
First received: September 19, 2012
Last updated: November 20, 2012
Last verified: November 2012
History of Changes
  Purpose

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.


Condition Intervention Phase
Hereditary Sensory and Autonomic Neuropathy Type I
 Drug: L-serine
Drug: placebo
 Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of L-Serine in Subjects With Hereditary Sensory Neuropathy Type 1

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • Charcot Marie Tooth Neuropathy Score [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    a 36 point functional rating scale


Secondary Outcome Measures:
  • Measures of intraepidermal nerve fiber density (IENFD) on skin biopsy [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Measures of sensory and autonomic testing [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • plasma measures of desoxysphingoid bases [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: January 2013
Estimated Study Completion Date: January 2017
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Sugar pill
Placebo arm
 Drug: placebo
400mg/kg/d divided TID for year 1 only.
Other Name: sugar pill
Active Comparator: L-serine
amino acid supplementation with L-serine
 Drug: L-serine
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.
Other Name: amino acid supplementation with L-serine

Detailed Description:

The study objective is to evaluate the efficacy of L-serine in subjects with hereditary sensory neuropathy type 1 (HSAN1). Hereditary sensory and autonomic neuropathy type I (HSAN1) is a progressive and debilitating illness for which currently no treatment exists. The investigators recently identified two novel deoxysphingoid bases (DSB) that accumulate in plasma of HSAN1 patients and mutant transgenic HSAN1 mice. The disease is caused by missense mutations in the SPTLC1 gene encoding a subunit of the enzyme serine palmitoyltransferase (SPT). In normal circumstances the SPT enzyme catalyzes the reaction of palmitoyl-CoA with serine to form sphinganine. The two newly identified DSB, deoxysphinganine and deoxymethylsphinganine, arise from condensation of palmitoyl-CoA with alanine and glycine respectively, suggesting that HSAN1 mutations alter amino acid selectivity of SPT. In support of this hypothesis the investigators have shown that levels of DSB in humans and mice can be lowered by supplementation with the enzyme's normal substrate, serine.

In this randomized, double-blind, placebo-controlled study the investigators will enroll 20 research participants with HSAN1 with 10 subjects assigned to L-serine (400mg/kg/d) and 10 assigned to placebo who are each treated for 24 months. The progression of HSAN1 will be measured by the change in an established clinical rating scale and measures of intraepidermal nerve fiber density (IENFD) on skin biopsy. The investigators will assess the percentage of failures (clinical decline of > 1 point on CMTNS or > 30% decrease in IENFD) at 6 month intervals. If patients in the placebo arm fail, they will be switched to L-serine.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HSAN1 patients with prominent sensory loss with foot ulcers or shooting pains and con-firmed mutations in SPTLC1.
  • Males and females of more than 18 years of age
  • 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.

Exclusion Criteria:

  • 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.
  • Patients who are unable or unwilling to give consent will not be enrolled in the study.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01733407

Locations
United States, Massachusetts
Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Jessica Pan, BS     617-643-3799     jpan3@partners.org    
Principal Investigator: Florian Eichler, MD            
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
Principal Investigator: Florian S Eichler, MD Massachusetts General Hospital
  More Information

Publications:

Responsible Party: Florian Eichler, Assistant Professor of Neurology, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT01733407     History of Changes
Other Study ID Numbers: FD-R-04127-01
Study First Received: September 19, 2012
Last Updated: November 20, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Massachusetts General Hospital:
inherited neuropathies

Additional relevant MeSH terms:
Hereditary Sensory and Autonomic Neuropathies
Nervous System Diseases
Demyelinating Diseases
Polyneuropathies
Nerve Compression Syndromes
Neurologic Manifestations
Neurotoxicity Syndromes
Polyradiculoneuropathy
Autoimmune Diseases of the Nervous System
Nervous System Malformations
Heredodegenerative Disorders, Nervous System
 Neurodegenerative Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Congenital Abnormalities
Genetic Diseases, Inborn
Autoimmune Diseases
Immune System Diseases
Signs and Symptoms
Poisoning
Substance-Related Disorders

ClinicalTrials.gov processed this record on May 19, 2013