L-Serine Supplementation in Hereditary Sensory Neuropathy Type 1

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01733407
Recruitment Status : Completed
First Posted : November 27, 2012
Last Update Posted : July 14, 2017
Information provided by (Responsible Party):
Florian Eichler, Massachusetts General Hospital

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

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

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 cross over 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 12 months. The 10 subjects assigned to placebo will then be crossed over to active L-serine for the remaining 12 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. L-serine levels will be measured using 24-hour pharmacokinetic blood sample at 12-month intervals. The investigators will assess the percentage of failures (clinical decline of > 1 point on CMTNS or > 30% decrease in IENFD) at 6 month intervals. Regardless of CMTNS score, all subjects who are on placebo for the first year will be switched to active study drug in year two.

After the 2 year period subjects will be given the option of being re-consented for the open label extension. All consented subjects will then be treated with L-serine (400 mg/kg/d) for an additional year.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, 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
Study Start Date : September 2013
Actual Primary Completion Date : May 2017
Actual Study Completion Date : July 2017

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. Charcot Marie Tooth Neuropathy Score [ Time Frame: 2 years ]
    a 36 point functional rating scale

Secondary Outcome Measures :
  1. Measures of intraepidermal nerve fiber density (IENFD) on skin biopsy [ Time Frame: 2 years ]
  2. Measures of sensory and autonomic testing [ Time Frame: 2 years ]
  3. plasma measures of desoxysphingoid bases [ Time Frame: 2 years ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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.

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.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01733407

United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
UMass Medical Center
Worcester, Massachusetts, United States, 01605
Sponsors and Collaborators
Massachusetts General Hospital
Principal Investigator: Florian S Eichler, MD Massachusetts General Hospital

Responsible Party: Florian Eichler, Assistant Professor of Neurology, Massachusetts General Hospital Identifier: NCT01733407     History of Changes
Other Study ID Numbers: FD-R-04127-01
First Posted: November 27, 2012    Key Record Dates
Last Update Posted: July 14, 2017
Last Verified: July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Florian Eichler, Massachusetts General Hospital:
inherited neuropathies

Additional relevant MeSH terms:
Peripheral Nervous System Diseases
Hereditary Sensory and Autonomic Neuropathies
Neuromuscular Diseases
Nervous System Diseases
Nervous System Malformations
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Congenital Abnormalities
Genetic Diseases, Inborn