Hereditary Sensory and Autonomic Neuropathy Type IPhase 1/2NCT01733407
L-Serine Supplementation in Hereditary Sensory Neuropathy Type 1
A Phase 1/2 study testing L-serine in people with Hereditary Sensory and Autonomic Neuropathy Type I, run by Massachusetts General Hospital at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hereditary Sensory and Autonomic Neuropathy Type I
- What is being tested?
- L-serine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 18 participants
- Where
- 2 sitesUnited States
- Study dates
- Sep 2013to Jul 2017
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 9Show fewer
- 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.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114
UMass Medical Center
Worcester, Massachusetts, 01605
About this study
Official title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of L-Serine in Subjects With Hereditary Sensory Neuropathy Type 1
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
Read the 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.
- Being tested
- L-serine, placebo
- Keywords
- inherited neuropathies
- Medical subject headings
- Hereditary Sensory and Autonomic Neuropathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-serineDrug
Also called amino acid supplementation with 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.
placeboDrug
Also called sugar pill
400mg/kg/d divided TID for year 1 only.
| Study group | Role | What they receive |
|---|---|---|
| Sugar pill | Placebo comparator | Placebo arm Receives: Drug: placebo |
| L-serine | Active comparator | amino acid supplementation with L-serine Receives: Drug: L-serine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 48 Weeks
Secondary outcomes (5)
Intraepidermal Nerve Fiber Density (IENFD)
Counts of nerve fibers per unit area in skin biopsies
Measured: 48 Weeks
Autonomic Function Testing (AFT) Composite Autonomic Severity Score (CASS)
Autonomic Function Testing (AFT) tests the effectiveness of your autonomic nervous system which regulates important functions such as blood pressure, heart rate, and respiration. AFT results are quantified using the composite autonomic severity score scale (CASS) which is a scale from 0 to 10 that is the sum of three sub scores (cardiovagal, adrenergic, and sudomotor). Cardiovagal is scored from 0 to 3, sudomotor is scored from 0 to 3, and adrenergic is scored from 0 to 4. The tests include deep breathing, Valsalva maneuver, head-up tilt, and a sweat test. The three subscores are then summed. This total represents the CASS which classifies autonomic function as normal functioning (total score 0), mild (total score 1-3), moderate (total score 4-6), or severe (total score 7-10).
Measured: 48 Weeks
Nerve Conduction Testing
Evaluates the functioning of electrical conduction of the motor and sensory nerves of the human body.
Measured: 48 Weeks
1-deoxy-sphinganine
Plasma levels of the deoxysphingoid lipid 1-deoxy-sphinganine measured by liquid chromatography/mass spectrometry after hydrolyzing the N-acyl and O-linked headgroups
Measured: 48 Weeks
1-deoxy-sphingosine
Plasma levels of the deoxysphingoid lipid 1-deoxy-sphingosine measured by liquid chromatography/mass spectrometry after hydrolyzing the N-acyl and O-linked headgroups
Measured: 48 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Nov 2012 (estimated)
- Study startSep 2013
- Primary completionMay 2016
- Study completionJul 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Hereditary Sensory and Autonomic Neuropathy Type IStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Florian Eichler, Massachusetts General Hospital
- Investigators
- Florian S Eichler, MD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01733407
- Sponsor's protocol ID
- FD-R-04127-01
- Status last verified
- Aug 2018
- First submitted
- 19 Sep 2012
- Last updated
- 12 Sep 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
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.
PubMed 22045570Fridman 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.
PubMed 30626650
Study at a glance
From the registry record, last updated by the sponsor on 12 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of L-Serine in Subjects With Hereditary Sensory Neuropathy Type 1
- ClinicalTrials.gov ID
- NCT01733407
- Acronym / sponsor ID
- FD-R-04127-01
- Keywords
- inherited neuropathies
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Study start
- Sep 2013
- Primary completion
- May 2016 (actual)
- Study completion
- Jul 2017 (actual)
- First posted
- 27 Nov 2012 (estimated)
- Results
- Posted 12 Sep 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Sugar pill | Placebo comparator | Drug: placeboPlacebo arm |
| L-serine | Active comparator | Drug: L-serineamino acid supplementation with L-serine |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-serineAlso: amino acid supplementation with L-serine400mg/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. | Drug | L-serine |
| placeboAlso: sugar pill400mg/kg/d divided TID for year 1 only. | Drug | Sugar pill |
Primary outcome
Charcot Marie Tooth Neuropathy Score
Time frame: 48 Weeks
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
5 secondary outcomes
Intraepidermal Nerve Fiber Density (IENFD)
Time frame: 48 Weeks
Autonomic Function Testing (AFT) Composite Autonomic Severity Score (CASS)
Time frame: 48 Weeks
Nerve Conduction Testing
Time frame: 48 Weeks
1-deoxy-sphinganine
Time frame: 48 Weeks
1-deoxy-sphingosine
Time frame: 48 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Sep 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 22045570Garofalo 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.
- Derived from this study: PubMed 30626650Fridman 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Florian S Eichler, MD principal investigator
Massachusetts General Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing L-serine in people with Hereditary Sensory and Autonomic Neuropathy Type I, run by Massachusetts General Hospital at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Sep 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Charcot Marie Tooth Neuropathy Score (time frame: 48 Weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01733407, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Sep 2018.